Heterocyclic modulators of lipid synthesis

ABSTRACT

Compounds that are fatty acid synthesis modulators are provided. The compounds may be used to treat disorders characterized by disregulation of the fatty acid synthase function by modulating the function and/or the fatty acid synthase pathway. Methods are provided for treating such disorders including viral infections, such as hepatitis C infection, cancer and metabolic disorders.

RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. provisionalapplication No. 62/135,631, filed Mar. 19, 2015, the entire contents ofwhich are incorporated herein by reference in its entirety.

FIELD

The present disclosure relates generally to heterocyclic modulators oflipid synthesis and methods of use thereof. The present heterocyclicmodulators of lipid synthesis can be used for the treatment of disorderscharacterized by disregulation in the fatty acid synthase function in asubject by modulating the fatty acid synthase pathway and/or the fattyacid synthase function.

BACKGROUND

Viral disease is a significant health concern that threatens largesegments of human populations. Some of the features related to viralinfection which are of concern to health care professionals include itshighly contagious nature (i.e., HIV, SARS, etc.) and high mutability.Some viruses are also oncogenic (such as HPV, EBV and HBV). Whileviruses are structurally amongst the simplest of organisms, they areregarded to be among the most difficult to control and present aformidable challenge for antiviral drug R&D.

Thus far, there have been a few antiviral drugs widely used in patients,such as Amantadine and Oseltamivir for influenza, Acyclovir forHSV-related infections, Ganciclovir for CMV infection, and multipleagents including co-formulated drugs (Efavirenz, emtricitabine, andtonfovir disoproxil fumarate) for AIDS treatments. These drugs possess avariety of undesirable neurological, metabolic and immunologicalside-effects. Therefore, development of new antiviral therapy has becomea major focus of medical and pharmaceutical research and development.

Infection by hepatitis C virus (HCV) is a serious health issue. It isestimated that 170 million people worldwide are chronically infectedwith HCV. HCV infection can lead to chronic hepatitis, cirrhosis, liverfailure and hepatocellular carcinoma. Chronic HCV infection is thus amajor worldwide cause of liver-related premature mortality.

The present standard of care treatment regimen for HCV infectioninvolves combination therapy with interferon-alpha and ribavirin, oftenwith the addition of a direct-acting protease inhibitor (Telaprevir orBoceprevir). The treatment is cumbersome and sometimes has debilitatingand severe side effects. For this reason, many patients are not treatedin early stages of the disease. Additionally, some patient populationsdo not durably respond to treatment. New and effective methods oftreating HCV infection are urgently needed.

The dominant therapeutic approaches that are currently employed to treatcancer include surgical removal of primary tumors, tumor irradiation,and parenteral application of anti-mitotic cytotoxic agents.Unfortunately, only a relatively small cross-section of cancer patientshave tumors that are “addicted” to a specific pathway, and can thereforebe treated with newer targeted agents. The continued dominance of theselong established therapies is mirrored by the lack of improvement insurvival rates for most cancers. In addition to limited clinicalsuccess, devastating side effects accompany classic therapies. Bothradiation- and cytotoxic-based therapies result in the destruction ofrapidly dividing hematopoietic and intestinal epithelial cells leadingto compromised immune function, anemia, and impaired nutrientabsorption. Surgical intervention often results in a release of tumorcells into the circulation or lymph systems from which metastatic tumorscan subsequently be established. Improved methods for the treatment ofcancer are needed.

SUMMARY

The present disclosure addresses the deficiencies for antiviral andanticancer treatments by providing novel heterocyclic modulators oflipid synthesis having improved antiviral and anticancer activities.

In various aspects, the present disclosure provides for compounds ofFormula (I):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent.    -   A is CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₅, R₉ R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   n is 1 or 2; and    -   m is 0 or 1.

In various aspects, the present disclosure provides for compounds ofFormula (II):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   L and D are each independently C or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R_(R), —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy,        —S(═O)₂R₂₀, or R₄ and R₁₁ taken together with the atoms to which        they are attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉ R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   n is 1 or 2; and    -   m is 0 or 1.

In various aspects, the present disclosure provides for compounds ofFormula (III):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   Q is C or N;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or if Q        is N then R₃ is absent;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₅, R₆, R₇, R₈, R₉ R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   R₁₉ is aryl, heteroaryl, cycloalkyl, or heterocyclyl;    -   n is 0, 1, or 2; and    -   m is 0 or 1.

In various aspects, the present disclosure provides for compounds ofFormulae (IV-A), (IV-B), or (IV-C):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L₁, L₂, L₃, L₄, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₃ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, is        absent if L₁ is N, or R₂₃ and R₂₄ taken together with the atoms        to which they are attached join together to form a heterocyclyl,        heteroaryl, or cycloalkyl;    -   R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆        alkoxy)(heterocyclyl), heterocyclyl, or R₂₃ and R₂₄ taken        together with the atoms to which they are attached join together        to form a heterocyclyl, heteroaryl, or cycloalkyl;    -   R₂₆ is hydrogen, heteroaryl, heterocyclyl. —N(R₁₃)(R₁₄), or        —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In various aspects, the present disclosure provides for compounds ofFormula (V):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L₇ is N or O, wherein R₃₀ is absent if L₇ is O:    -   A is CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₉ and R₃₀ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, —N(R₁₅R₁₆),        —C(═O)R₄₆, —R₄₈C(═O)R₄₇, or R₂₉ and R₃₀ taken together with the        atoms to which they are attached join together to form a        heteroaryl or heterocyclyl, wherein R₃₀ is absent if L₇ is O;    -   R₄₆ and R₄₇ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₄₈ is alkyl or is absent;    -   R₃₁ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino; and    -   v is 0 or 1.

In various aspects, the present disclosure provides for compounds ofFormulae (VI-A) or (VI-B):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L₁₃, L₁₄, L₁₅, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cycloalkyl, hydroxyl,        hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino. CF₃,        —OCF₃, —S(═O)₂R₂₀, or —N(R₁₅R₁₆);    -   R₃₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃₆ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₅R₁₆),        heterocyclyl, or heteroaryl;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In various aspects, the present disclosure provides for compounds ofFormula (VI-J):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently H, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and    -   R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl,        heterocyclyl, aryl or heteroaryl.

In some aspects of Formula (VI-J), R³ is H or halogen.

In some aspects of Formula (VI-J), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Formula (VI-J), R²² is C₁-C₂ alkyl.

In some aspects of Formula (VI-J), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Formula (VI-J), R²¹ is cyclobutyl.

In some aspects of Formula (VI-J), R³ is H or F.

In some aspects of Formula (VI-J), R¹ is —CN.

In some aspects of Formula (VI-J), R¹ is —CF₃.

In some aspects of Formula (VI-J), R²² is H, methyl or ethyl.

In some aspects of Formula (VI-J), R²² is H.

In some aspects of Formula (VI-J), R²² is methyl.

In some aspects of Formula (VI-J), R³⁵ is —C(O)—NHR³⁵¹.

In some aspects of Formula (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Formula (VI-J), R³⁵¹ is(R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some aspects of Formula (VI-J), R¹ is —CN, each R² is hydrogen, R³ isH or F, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—NHR³⁵¹ whereR³⁵¹ is isopropyl, isobutyl, (R)-3-tetrahydrofuranyl,(S)-3-tetrahydrofuranyl, (R)-(tetrahydrofuran-2-yl)methyl,(S)-(tetrahydrofuran-2-yl)methyl, (R)-tetrahydro-2H-pyran-3-yl, or(S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Formula (VI-J), R³⁵ is —C(O)—O—R³⁵¹.

In some aspects of Formula (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Formula (VI-J), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³³ is —C(O)—O—R³⁵¹ where R³⁵¹ isisopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Formula (VI-J), R³⁵¹ is (R)-3-tetrahydrofuranyl or(S)-3-tetrahydrofuranyl.

In some aspects of Formula (VI-J), compounds have a Formula selectedfrom the group consisting of:

In various aspects, the present disclosure provides for compounds ofFormulae (VII-A) or (VII-B):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L₁₆ is C or N, wherein R₄₁ is absent if L₁₆ is N;    -   L₁₇, L₁₈, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₄₀, R₄₂, and R₄₃ are each independently hydrogen, C₁₋₆ alkyl,        C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R, hydroxyalkyl, hydroxyl,        —N(R₁₃R₁₄), or R₄₁ and R₄₂ taken together with the atoms to        which they are attached join together to form a heteroaryl or        heterocyclyl;    -   R₄₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R,        hydroxyalkyl, hydroxyl, —N(R₁₃R₁₄), R₄₁ is absent if L₁₆ is N.        or R₄₁ and R₄₂ taken together with the atoms to which they are        attached join together to form a heteroaryl or heterocyclyl;    -   R is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino.

In various aspects, the present disclosure provides for compounds ofFormulae (VIII-A), (VIII-B), or (VIII-C):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L₁₉ and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4,    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₄₄ and R₄₅ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, hydroxyalkyl, aryl, heterocyclyl,        heteroaryl, alkylamino. —S(═O)₂R₂₀, —C(O)R, or —N(R₁₃R₁₄); and    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino.

In various aspects, compounds of Formula (IX) are provided:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃—C        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄        alkyl)_(t)-OH,        -   —(C₁-C₄ alkyl)_(t)-O_(t)-(C₃-C₅ cycloalkyl), or        -   —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl)            wherein:            -   t is 0 or 1;            -   the C₃-C₅ cycloalkyl optionally includes an oxygen or                nitrogen heteroatom;    -   L¹ is CR²³ or N;    -   L² is CH or N;    -   at least one of L¹ or L² is N; and    -   R²³ is H or C₁-C₄ straight or branched alkyl.

In some aspects of Formula (IX), R²⁴ is C₁-C₄ straight or branched alkylor —(C₁-C₄ alkyl)-O—(C₁-C₄ straight or branched alkyl) wherein t is 0 or1.

In some aspects of Formula (IX), R²¹ is halogen, C₁-C₄ straight orbranched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom, —S(O)_(u)—(C₁-C₄ straight orbranched alkyl) wherein u is 0 or 2, or —S(O)_(u)—(C₃-C₅ cycloalkyl)wherein u is 0 or 2;

In some aspects of Formula (IX), R³ is H or halogen.

In some aspects of Formula (IX), R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some aspects of Formula (IX), both L¹ and L² are N.

In some aspects of Formula (IX), R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyland R² is C₁-C₂ alkyl.

In some aspects of Formula (IX), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Formula (IX), R²⁴ is —(C₁-C₂ alkyl)-O—(C₁-C₂ alkyl)wherein t is 0 or 1.

In some aspects of Formula (IX), R²¹ is C₃-C₅ cycloalkyl, R²² is C₁-C₂alkyl and R²⁴ is C₁-C₂ alkyl.

In some aspects of Formula (IX), R²¹ is cyclobutyl, R²² is C₁-C₂ alkyland R²⁴ is C₁-C₂ alkyl.

In some aspects of Formula (IX), R²¹ is cyclobutyl.

In some aspects of Formula (IX), R³ is H or F.

In some aspects of Formula (IX), R¹ is —CN.

In some aspects of Formula (IX), R¹ is —CF₃.

In some aspects of Formula (IX), R²² is H, methyl or ethyl.

In some aspects of Formula (IX), R²² is H.

In some aspects of Formula (IX), R²² is methyl.

In some aspects of Formula (IX), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl. R²² is methyl. L¹ and L² are N, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl.

In some aspects of Formula (IX), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ ismethoxy or ethoxy.

In some aspects of Formula (IX), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is CH, L² is N, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Formula (IX), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is N, L² is CH, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Formula (IX), compounds have a Formula selected fromthe group consisting of:

In various aspects, compounds of Formula (X) are provided:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:    -   the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen        heteroatom; and    -   when R¹ is not H, —CN or halogen, it is optionally substituted        with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH or halogen;    -   L³ is C(R₆)₂, O or NR³⁰;    -   each R is independently H, —OH, —CN, —O—(C₃-C₅ cycloalkyl).        —O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R⁶⁰¹)₂        wherein:        -   t is 0 or 1, and the C₃-C₅ cycloalkyl optionally includes an            oxygen or nitrogen heteroatom;    -   each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or        branched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic        alkyl optionally containing an oxygen or nitrogen heteroatom,        —C(O)—N(R⁵⁰¹)₂, C₁-C₄ straight or branched alkyl wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   n is 1, 2 or 3;    -   m is 1 or 2;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl;    -   each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or        branched alkyl. —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl),        —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl),        —C(O)—O_(t)-(C₁-C₄ alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   s is 0, 1 or 2;    -   each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or        branched alkyl; and    -   wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to        form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may        be two R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹.

In some aspects of Formula (X), R₂₁ is halogen, C₁-C₄ straight orbranched alkyl or C₃-C₅ cycloalkyl.

In some aspects of Formula (X), R¹ is H or halogen.

In some aspects of Formula (X), R¹ is —CN or C₁-C₂ haloalkyl.

In some aspects of Formula (X), R³ is H or F.

In some aspects of Formula (X), R¹ is —CN.

In some aspects of Formula (X), R¹ is —CF₃.

In some aspects of Formula (X), n is 1.

In some aspects of Formula (X), n is 2.

In some aspects of Formula (X), m is 1

In some aspects of Formula (X), m is 2.

In some aspects of Formula (X), R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyland R²² is C₁-C₂ alkyl.

In some aspects of Formula (X), R²¹ is C₃-C₅ cycloalkyl and R²² is C₁-C₂alkyl.

In some aspects of Formula (X), n is 2, m is 1, L³ is —N—C(O)—O—(C₁-C₂alkyl).

In some aspects of Formula (X), L³ is NR⁵⁰; R³⁰ is C₁-C₂ alkyl; R²¹ iscyclobutyl; R²² is H or methyl; R³ is H; R¹ is —CN; m is 2 and n is 1 or2.

In some aspects of Formula (X), n is 2, m is 1, L³ is O and s is 0.

In some aspects of Formula (X), R²² is H, methyl or ethyl.

In some aspects of Formula (X), R²² is methyl.

In some aspects of Formula (X), R²² is H.

In some aspects of Formula (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is NR⁵⁰ where R⁵⁰is methyl or ethyl.

In some aspects of Formula (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L³ is O.

In some aspects of Formula (X), the compound has a Formula selected fromthe group consisting of:

In various aspects, compounds of Formula (XI) are provided:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently H, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;    -   R²² is H, halogen, C₁-C₂ alkyl; and    -   R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In some aspects of Formula (XI), R³ is H or halogen.

In some aspects of Formula (XI), R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some aspects of Formula (XI), R²¹ is C₃-C₄ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Formula (XI), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Formula (XI), R²¹ is cyclobutyl.

In some aspects of Formula (XI), R³ is H or F.

In some aspects of Formula (XI), R¹ is —CN.

In some aspects of Formula (XI), R¹ is —CF₃.

In some aspects of Formula (XI), R²² is H, methyl or ethyl.

In some aspects of Formula (XI), R²² is H.

In some aspects of Formula (XI), R²² is methyl.

In some aspects of Formula (XI), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is cyclobutyl, R²² is methyl and R³⁵¹ is methyl or ethyl.

In some aspects of Formula (XI), the compound has a Formula selectedfrom the group consisting of:

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Formulae (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) and apharmaceutically acceptable carrier, excipient, or diluent.

In various aspects, the present disclosure provides methods of treatinga condition characterized by disregulation of a fatty acid synthasefunction in a subject, the method comprising administering to thesubject in need of such treatment an effective amount of a compound ofany one of the Formulae (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X) or (XI). In various aspects, the conditioncharacterized by disregulation of the fatty acid synthase function is aviral infection or cancer. In various aspects, the viral infection istreated using a compound of any one of the Formulae (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) in combination withone or more additional antiviral treatments. In various aspects thecancer is treated using a compound of any one of the Formulae (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) in combinationwith one or more additional cancer treatments. In various aspects, theviral infection is hepatitis C.

In various aspects, the present disclosure provides methods of treatingcancer in a subject, the method comprising administering to the subjectin need of such treatment an effective amount of a compound of any oneof the Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX),(X) or (XI).

In various aspects, the present disclosure provides methods of treatinga condition characterized by disregulation of a fatty acid synthasepathway in a subject, the method comprising administering to the subjectin need of such treatment an effective amount of:

(i) a first therapeutic agent, wherein the first therapeutic agent iscompound of Formula (IX):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₄        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄        alkyl)_(t)-OH,        -   —(C₁-C₄ alkyl)_(t)-O_(t)-(C₃-C₅ cycloalkyl), or        -   —(C₁-C₄ alkyl), —O—(C₁-C₄ straight or branched alkyl)            wherein:            -   t is 0 or 1:            -   the C₃-C₅ cycloalkyl optionally includes an oxygen or                nitrogen heteroatom;    -   L¹ is CR²³ or N;    -   L² is CH or N;    -   at least one of L¹ or L² is N; and    -   R²³ is H or C₁-C₄ straight or branched alkyl; and

(ii) a second therapeutic agent.

In various aspects, the present disclosure provides a compound of anyone of the Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X) or (XI) for use in treating a condition characterized bydisregulation of a fatty acid synthase function in a subject. In variousaspects the condition characterized by disregulation of the fatty acidsynthase function is a viral infection or cancer. In various aspects,the viral infection is treated using a compound of any one of theFormulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or(XI) in combination with one or more additional antiviral treatments. Invarious aspects, the cancer is treated using a compound of any one ofthe Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X)or (XI) in combination with one or more additional cancer treatments. Invarious aspects, the viral infection is hepatitis C.

In various aspects, the present disclosure provides a compound of anyone of the Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X) or (XI) for use in treating cancer in a subject.

In various aspects, the present disclosure provides

(i) a first therapeutic agent, wherein the first therapeutic agent iscompound of Formula (IX):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R²¹ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄        alkyl)_(t)-OH,        -   —(C₁-C₄ alkyl)_(t)-O_(t)-(C₃-C₅ cycloalkyl), or        -   —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl)            wherein:            -   t is 0 or 1;            -   the C₃-C₅ cycloalkyl optionally includes an oxygen or                nitrogen heteroatom;    -   L¹ is CR²³ or N;    -   L² is CH or N;    -   at least one of L¹ or L² is N; and    -   R²³ is H or C₁-C₄ straight or branched alkyl; and

(ii) a second therapeutic agent;

for use in treating a condition characterized by disregulation of afatty acid synthase function in a subject.

In various aspects, the present disclosure provides the use of acompound of any one of the Formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X) or (XI) in the treatment of a conditioncharacterized by disregulation of a fatty acid synthase function in asubject. In various aspects, the condition characterized bydisregulation of the fatty acid synthase function is a viral infectionor cancer. In various aspects the viral infection is treated using acompound of any one of the Formulae (I), (II), (II), (IV), (V), (VI),(VII), (VIII), (IX), (X) or (XI) in combination with one or moreadditional antiviral treatments. In various aspects, the cancer istreated using a compound of any one of the Formulae (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) in combination withone or more additional cancer treatments. In various aspects, the viralinfection is hepatitis C.

In various aspects, the present disclosure provides the use of acompound of any one of the Formulae (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X) or (XI) in the treatment of cancer in asubject.

In various aspects, the present disclosure provides the use of

(i) a first therapeutic agent, wherein the first therapeutic agent iscompound of Formula (IX):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)-OH,        -   —(C₁-C₄ alkyl)-O_(t)—(C₃-C₅ cycloalkyl), or        -   —(C₁-C₄ alkyl)-O—(C₁-C₄ straight or branched alkyl) wherein:            -   t is 0 or 1;            -   the C₃-C₅ cycloalkyl optionally includes an oxygen or                nitrogen heteroatom:    -   L¹ is CR²³ or N;    -   L² is CH or N;    -   at least one of L¹ or L¹ is N; and    -   R²³ is H or C₁-C₄ straight or branched alkyl; and

(ii) a second therapeutic agent;

in the treatment of a condition characterized by disregulation of afatty acid synthase function in a subject.

In various aspects, the present disclosure provides the a compound ofany one of the Formulae (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X) or (XI) for use in the manufacture of a medicament fortreating of a condition characterized by disregulation of a fatty acidsynthase function in a subject. In various aspects, the conditioncharacterized by disregulation of the fatty acid synthase function is aviral infection or cancer. In various aspects, the viral infection istreated using a compound of any one of the Formulae (I), (II), (III),(IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) in combination withone or more additional antiviral treatments. In various aspects, thecancer is treated using a compound of any one of the Formulae (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) in combinationwith one or more additional cancer treatments. In various aspects, theviral infection is hepatitis C.

In various aspects, the present disclosure provides a compound of anyone of the Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X) or (XI) for use in the manufacture of a medicament fortreating cancer in a subject.

In various aspects, the present disclosure provides

(i) a first therapeutic agent, wherein the first therapeutic agent iscompound of Formula (IX):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₃ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄        alkyl)_(t)-OH,        -   —(C₁-C₄ alkyl)_(t)-O_(t)-(C₃-C₅ cycloalkyl), or        -   —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl)            wherein:            -   t is 0 or 1;            -   the C₃-C₅ cycloalkyl optionally includes an oxygen or                nitrogen heteroatom;    -   L¹ is CR²³ or N;    -   L² is CH or N;    -   at least one of L¹ or L² is N; and    -   R²³ is H or C₁-C₄ straight or branched alkyl; and

(ii) a second therapeutic agent;

for use in the manufacture of a medicament for treating a conditioncharacterized by disregulation of a fatty acid synthase function in asubject.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a correlation between FASN inhibition and HCVinhibition.

DETAILED DESCRIPTION

The present disclosure addresses the deficiencies in treating conditionscharacterized by disregulation of the FASN function in a subject, suchas viral infection, cancer and metabolic disorders, by providing novelheterocyclic modulators of lipid synthesis.

In certain aspects, the present disclosure provides compositions andmethods for treatment of viral infections. In general, the compositionsand methods for treatment of viral infections are directed towardmodulation of the fatty acid synthesis pathway. The fatty acid synthesispathway is involved in the replication of viruses into the host cells.The present invention embodies methods for the treatment of viralinfection, such as hepatitis C infections, yellow fever infections, andhuman rhinovirus infections, or any virus that targets the fatty acidsynthesis pathway.

In certain aspects, the present disclosure provides compositions andmethods for the treatment of cancer. Fatty acid synthase is responsiblefor conversion of malonyl-CoA into long-chain fatty acids, which is anearly reaction in fatty acid biosynthesis. Fatty acid synthase isoverexpressed in many cancer cells. Without being bound by anyparticular theory, it is hypothesized that inhibition of fatty acidsynthase expression or fatty acid synthase activity selectivitysuppresses proliferation and induces cell death of cancer cells, withlittle toxicity towards normal cells.

Further, the present disclosure provides compounds and methods formodulating host cell targets that are targeted by viruses. Suchmodulation of host cell targets can include either activation orinhibition of the host cell targets. Accordingly, compounds thatmodulate, i.e., inhibit, the activity of a non-viral protein, i.e., ahost cell protein, i.e., components of the fatty acid synthesis pathway,can be used as antiviral pharmaceutical agents.

Definitions

Chemical moieties referred to as univalent chemical moieties (i.e.,alkyl, aryl, etc.) also encompass structurally permissible multivalentmoieties, as understood by those skilled in the art. For example, whilean “alkyl” moiety generally refers to a monovalent radical (i.e.,CH₃CH₂—), in appropriate circumstances an “alkyl” moiety can also referto a divalent radical (i.e., —CH₂CH₂—, which is equivalent to an“alkylene” group). Similarly, under circumstances where a divalentmoiety is required, those skilled in the art will understand that theterm “aryl” refers to the corresponding divalent arylene group.

All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the atom's oxidation state). On occasion a moiety can bedefined, for example, as (A)_(a)B, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B and when a is 1 the moiety is AB.

Where a substituent can vary in the number of atoms or groups of thesame kind (i.e., alkyl groups can be C₁, C₂, C₃, etc.), the number ofrepeated atoms or groups can be represented by a range (i.e., C₁-C₆alkyl) which includes each and every number in the range and any and allsub ranges. For example, C₁-C₃ alkyl includes C₁, C₂, C₃, C₁₋₂, C₁₋₃,and C₂₋₃ alkyl.

“Alkanoyl” refers to a carbonyl group with a lower alkyl group as asubstituent.

“Alkylamino” refers to an amino group substituted by an alkyl group.

“Alkoxy” refers to an O-atom substituted by an alkyl group as definedherein, for example, methoxy [—OCH₃, a C₁alkoxy]. The term “C₁₋₆ alkoxy”encompasses C₁₋₆ alkoxy, C₂ alkoxy, C₃ alkoxy, C₄ alkoxy, C₅ alkoxy, C₆alkoxy, and any sub-range thereof.

“Alkoxycarbonyl” refers to a carbonyl group with an alkoxy group as asubstituent.

“Alkyl,” “alkenyl,” and “alkynyl,” refer to optionally substituted,straight and branched chain aliphatic groups having from 1 to 30 carbonatoms, or preferably from 1 to 15 carbon atoms, or more preferably from1 to 6 carbon atoms. Examples of alkyl groups include, withoutlimitation, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,isobutyl, pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, andpropynyl. The term “heteroalkyl” as used herein contemplates an alkylwith one or more heteroatoms.

“Alkylene” refers to an optionally substituted divalent radical which isa branched or unbranched hydrocarbon fragment containing the specifiednumber of carbon atoms, and having two points of attachment. An exampleis propylene [—CH₂CH₂CH₂—, a C₃alkylene].

“Amino” refers to the group —NH₂.

“Aryl” refers to optionally substituted aromatic groups which have atleast one ring having a conjugated pi electron system and includescarbocyclic aryl, and biaryl groups, all of which can be optionallysubstituted. Phenyl and naphthyl groups are preferred carbocyclic arylgroups.

“Aralkyl” or “arylalkyl” refer to alkyl-substituted aryl groups.Examples of aralkyl groups include butylphenyl, propylphenyl,ethylphenyl, methylphenyl, 3,5-dimethylphenyl, tert-butylphenyl.

“Carbamoyl” as used herein contemplates a group of the structure

where in R^(N) is selected from the group consisting of hydrogen, —OH,C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamide.

“Carbonyl” refers to a group of the structure

“Cycloalkyl” refers to an optionally substituted ring, which can besaturated or unsaturated and monocyclic, bicyclic, or tricyclic formedentirely from carbon atoms. An example of a cycloalkyl group is thecyclopentenyl group (C₅H₇—), which is a five carbon (C₅) unsaturatedcycloalkyl group.

“Heterocycle” refers to an optionally substituted 5- to 7-memberedcycloalkyl ring system containing 1, 2 or 3 heteroatoms, which can bethe same or different, selected from N, O or S, and optionallycontaining one double bond.

“Halogen” refers to a chloro, bromo, fluoro or iodo atom radical. Theterm “halogen” also contemplates terms “halo” or “halide.”

“Heteroatom” refers to a non-carbon atom, where boron, nitrogen, oxygen,sulfur and phosphorus are preferred heteroatoms, with nitrogen, oxygenand sulfur being particularly preferred heteroatoms in the compounds ofthe present disclosure.

“Heteroaryl” refers to optionally substituted aryl groups having from 1to 9 carbon atoms and the remainder of the atoms are heteroatoms, andincludes those heterocyclic systems described in “Handbook of Chemistryand Physics,” 49th edition, 1968, R. C. Weast, editor; The ChemicalRubber Co., Cleveland, Ohio. See particularly Section C, Rules forNaming Organic Compounds, B. Fundamental Heterocyclic Systems. Suitableheteroaryls include thienyl, pyrryl, furyl, pyridyl, pyrimidyl,pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl,pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, triazolyl,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl, oxadiazolyl,benzoxazolyl, benzoxadiazolyl, thiadiazolyl, benzothiazolyl,benzothiadiazolyl, and the like.

An “optionally substituted” moiety can be substituted with from one tofour, or preferably from one to three, or more preferably one or twonon-hydrogen substituents. Unless otherwise specified, when thesubstituent is on a carbon, it is selected from the group consisting of—OH, —CN, —NO₂, halogen, C₁ to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl,cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, substituted sulfonyl, sulfonate,sulfonamide and amino, none of which are further substituted. Unlessotherwise specified, when the substituent is on a nitrogen, it isselected from the group consisting of C₁ to C₁₂ alkyl, C₁ to C₁₂heteroalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, aralkyl, alkoxy,alkoxycarbonyl, alkanoyl, carbamoyl, sulfonyl, sulfonate and sulfonamidenone of which are further substituted.

The term “sulfonamide” as used herein contemplates a group having thestructure

wherein R^(N) is selected from the group consisting of hydrogen, —OH, C₁to C₁₂ alkyl, C₁ to C₁₂ heteroalkyl, alkenyl, alkynyl, cycloalkyl,heterocycle, aryl, heteroaryl, aralkyl, alkoxy, alkoxycarbonyl,alkanoyl, carbamoyl, substituted sulfonyl, sulfonate and sulfonamide.

The term “sulfonate” as used herein contemplates a group having thestructure

wherein R^(N) is selected from the group consisting of hydrogen, C₁-C₁₀alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₁-C₁₀ alkanoyl, or C₁-C₁₀alkoxycarbonyl.

“Sulfonyl” as used herein alone or as part of another group, refers toan SO₂ group. The SO₂ moiety is optionally substituted.

Compounds of the present disclosure can exist as stereoisomers, whereinasymmetric or chiral centers are present. Stereoisomers are designated(R) or (S) depending on the configuration of substituents around thechiral carbon atom. The terms (R) and (S) used herein are configurationsas defined in IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem., (1976), 45: 13-30, herebyincorporated by reference. The present disclosure contemplates variousstereoisomers and mixtures thereof and are specifically included withinthe scope of the present disclosure. Stereoisomers include enantiomers,diastereomers, and mixtures of enantiomers or diastereomers. Individualstereoisomers of compounds of the present disclosure can be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution well-known to those of ordinary skill inthe art. These methods of resolution are exemplified by (1) attachmentof a mixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and liberation of the optically pure product from theauxiliary or (2) direct separation of the mixture of optical enantiomerson chiral chromatographic columns.

Also, moieties disclosed herein which exist in multiple tautomeric formsinclude all such forms encompassed by a given tautomeric structure.

Individual atoms in the disclosed compounds may be any isotope of thatelement. For example hydrogen may be in the form of deuterium.

“Pharmaceutically acceptable” means approved or approvable by aregulatory agency of the Federal or state government or listed in theU.S. Pharmacopoeia or other generally recognized pharmacopoeia for usein animals, and more particularly in humans. It can be material which isnot biologically or otherwise undesirable, i.e., the material can beadministered to an individual without causing any undesirable biologicaleffects or interacting in a deleterious manner with any of thecomponents of the composition in which it is contained.

The term “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include, forexample, acid addition salts and base addition salts.

“Acid addition salts” according to the present disclosure, are formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or formedwith organic acids such as acetic acid, propionic acid, hexanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like.

“Base addition salts” according to the present disclosure are formedwhen an acidic proton present in the parent compound either is replacedby a metal ion, i.e., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine,tromethamine. N-methylglucamine, and the like. Acceptable inorganicbases include aluminum hydroxide, calcium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydroxide, and the like. It shouldbe understood that a reference to a pharmaceutically acceptable saltincludes the solvent addition forms or crystal forms thereof,particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature can cause asingle crystal form to dominate.

The term “treating” includes the administration of the compounds oragents of the present invention to a subject to prevent or delay, toalleviate, or to arrest or inhibit development of the symptoms orconditions associated with fatty acid synthase-associated disorders,i.e., tumor growth associated with cancer. A skilled medicalpractitioner will know how to use standard methods to determine whethera patient is suffering from a disease associated with activity of fattyacid synthase, i.e., by examining the patient and determining whetherthe patient is suffering from a disease known to be associated withfatty acid synthase activity or by assaying for fatty acid synthaselevels in blood plasma or tissue of the individual suspected ofsuffering from fatty acid synthase associated disease and comparingfatty acid synthase levels in the blood plasma or tissue of theindividual suspected of suffering from a fatty acid synthase associateddisease fatty acid synthase levels in the blood plasma or tissue of ahealthy individual. Increased securin levels are indicative of disease.Accordingly, the present invention provides, inter alia, methods ofadministering a compound of the present invention to a subject anddetermining fatty acid synthase activity in the subject. Fatty acidsynthase activity in the subject can be determined before and/or afteradministration of the compound.

A “therapeutically effective amount” or “pharmaceutically effectiveamount” means the amount that, when administered to a subject, produceseffects for which it is administered. For example, a “therapeuticallyeffective amount,” when administered to a subject to inhibit fatty acidsynthase activity, is sufficient to inhibit fatty acid synthaseactivity. A “therapeutically effective amount,” when administered to asubject for treating a disease, is sufficient to effect treatment forthat disease.

Except when noted, the terms “subject” or “patient” are usedinterchangeably and refer to mammals such as human patients andnon-human primates, as well as experimental animals such as rabbits,rats, and mice, and other animals. Accordingly, the term “subject” or“patient” as used herein means any mammalian patient or subject to whichthe compounds of the invention can be administered. In an exemplaryaspect of the present invention, to identify subject patients fortreatment according to the methods of the invention, accepted screeningmethods are employed to determine risk factors associated with atargeted or suspected disease or condition or to determine the status ofan existing disease or condition in a subject. These screening methodsinclude, for example, conventional work-ups to determine risk factorsthat are associated with the targeted or suspected disease or condition.These and other routine methods allow the clinician to select patientsin need of therapy using the methods and formulations of the presentinvention.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

Throughout this disclosure, various patents, patent applications andpublications are referenced. The disclosures of these patents, patentapplications and publications in their entireties are incorporated intothis disclosure by reference in order to more fully describe the stateof the art as known to those skilled therein as of the date of thisdisclosure. This disclosure will govern in the instance that there isany inconsistency between the patents, patent applications andpublications and this disclosure.

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. The initial definition provided for a group or termprovided in this disclosure applies to that group or term throughout thepresent disclosure individually or as part of another group, unlessotherwise indicated.

FASN Pathway Modulators

One aspect of the present disclosure includes a method of inhibitingviral infection or treating cancer by contacting a cell with an agentthat modulates the fatty acid synthesis pathway. This method ofinhibiting viral infection or treating cancer can be performed in vitroby contacting virally infected/cancerous cells with an agent thatmodulates the fatty acid synthesis pathway, or in vivo by administeringan agent that modulates the fatty acid synthesis pathway to a subjectinfected with a virus/having cancer. In one aspect, an agent can be aninhibitor of the fatty acid synthesis pathway.

Examples of inhibitors of the fatty acid synthesis pathway that can beused in the methods and compositions of the present disclosure aredescribed below.

Compounds of Formula (I)

In various aspects, the present disclosure provides for compounds ofFormula (I):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent.    -   A is CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₅, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   n is 1 or 2; and    -   m is 0 or 1.

In certain aspects of Formula (I), R₃ is F.

In certain aspects of Formula (I), A is CH.

In certain aspects of Formula (I), A is N.

In certain aspects of Formula (I), X, Y, and Z are NR′.

In certain aspects of Formula (I). R₄ is heteroaryl, heterocyclyl,—C(═O)N(R₅R₆), —N(R₇)C(═O)R₅, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₄and R₁₁ taken together with the atoms to which they are attached jointogether to form a heteroaryl.

In certain aspects of Formula (I), R₅ is hydrogen and R₆ is aryl orheteroaryl.

In certain aspects, the compounds of Formula (I) have one of thefollowing Formulae (I-A) or (I-B):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉ R₁₀, R₁₃, and R₁₄ are each independently        hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, or alkylamino; and    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond.

In certain aspects, the compounds of Formula (I) have one of thefollowing Formulae (I-C) or (I-D):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is        hydrogen or C₁₋₆ alkyl and R′ is hydrogen, C₁₋₆ alkyl, or        absent;    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Formula (I) have one of thefollowing Formulae (I-E), (I-F), (I-G), (I-H):

-   -   or a pharmaceutically acceptable salt thereof, wherein;    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁a alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂taken together        with the atoms to which they are attached join together to form        a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Formula (I) have one of thefollowing Formulae (I-I), (I-J), or (I-K):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Formula (I) have one of thefollowing Formulae (I-L) or (I-M):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C_(1i) alkyl, C₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆), and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Formula (I) have one of thefollowing Formulae (I-N) or (I-O):

-   -   or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Formula (I) have the followingFormula (I-P):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R_(T))C(═O)R₅, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy,        —S(═O)₂R₂₀, or R₄ and R₁₁ taken together with the atoms to which        they are attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Formula (I) have one of thefollowing Formulae (I-Q), (I-R), or (I-S)

-   -   or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Formula (I) have the followingFormula (I-T):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Formula (I) have the followingFormula (I-U):

-   -   or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Formula (I) have one of thefollowing Formulae (I-V):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl; R₁₂        is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₃R₁₄),        CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken together with the        atoms to which they are attached join together to form a        heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compound of Formula (I) has the followingFormula (I-W):

-   -   or a pharmaceutically acceptable salt thereof.

In certain aspects, the compounds of Formula (I) have one of thefollowing Formulae (I-X), (I-Y), (I-Z), (I-AA), (I-AB), (I-AC), (I-AD),(I-AF), (I-AG), or (I-AH):

-   -   or a pharmaceutically acceptable salt thereof.

Compounds of Formula (II)

In various aspects, the present disclosure provides for compounds ofFormula (II):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   L and D are each independently C or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆);    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   n is 1 or 2; and    -   m is 0 or 1.

In certain aspects, the compounds of Formula (II) have the followingFormula (II-A):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Formula (II) have the followingFormula (II-B):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀,        or R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Formula (II) have one of thefollowing Formulae (II-C), (II-D), or (II-E):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, C₁₋₆ alkyl, or R₂ and R₃        taken together with the atoms to which they are attached form a        5-membered heterocyclyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or R₂        and R₃ taken together with the atoms to which they are attached        form a 5-membered heterocyclyl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compound of Formula (II) has the followingFormula (II-F):

-   -   or a pharmaceutically acceptable salt thereof.

Compounds of Formula (III)

In various aspects, the present disclosure provides for compounds ofFormula (III):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X, Y, and Z are each independently CR or NR′, wherein R is H or        C₁₋₆ alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   Q is C or N;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or if Q        is N R₃ is absent;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R₇)C(═O)R, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, or        R₄ and R₁₁ taken together with the atoms to which they are        attached join together to form a heteroaryl;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl, or R₁₁ and R₁₂ taken together with the atoms to        which they are attached join together to form a heteroaryl;    -   R₁₂ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₁₁ and R₁₂ taken        together with the atoms to which they are attached join together        to form a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₃, and R₁₄ are each independently H,        C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl,        alkylamino, or —N(R₁₅R₁₆);    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino;    -   R₁₇ and R₁₈ are each independently hydrogen or alkyl or can        optionally join together to form a bond;    -   R₁₉ is aryl, heteroaryl, cycloalkyl, or heterocyclyl;    -   n is 0, 1, or 2; and    -   m is 0 or 1.

In certain aspects, the compounds of Formula (III) have one of thefollowing Formulae (III-A), (III-B), or (III-C):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X and Y are each independently CR or NR′, wherein R is H or C₁₋₆        alkyl and R′ is H, C₁₋₆ alkyl, or absent;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C_(1i) alkoxy;    -   R₄ is hydrogen, heteroaryl, heterocyclyl, —C(═O)N(R₅R₆),        —N(R_(T))C(═O)R₈, —N(R₉R₁₀), C₁₋₆ alkyl, C₁₋₆ alkoxy,        —S(═O)₂R₂₀, or R₄ and R₁₁ taken together with the atoms to which        they are attached join together to form a heteroaryl;    -   R₁₁ is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —N(R₁₃R₁₄), CF₃, —OCF₃, —S(═O)₂R₂₀, or R₄ and R₁₁ taken together        with the atoms to which they are attached join together to form        a heteroaryl;    -   R₅, R₆, R₇, R₈, R₉, and R₁₀ are each independently H, C₁₋₆        alkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkylamino,        or —N(R₁₅R₁₆); and    -   R₁₅ and R₁₆ are each independently H, C₁₋₆ alkyl, cycloalkyl,        aryl, heterocyclyl, heteroaryl, or alkylamino.

In certain aspects, the compounds of Formula (III) have one of thefollowing Formulae (III-D), (III-E), or (III-F):

-   -   or a pharmaceutically acceptable salt thereof.

Compounds of Formula (IV)

In certain aspects, the compounds of Formula (IV) have one of thefollowing Formulae (IV-A), (IV-B), or (IV-C):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L₁, L₂, L₃, L₄, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₃ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, is        absent if L₁ is N, or R₂₃ and R₂₄ taken together with the atoms        to which they are attached join together to form a heterocyclyl,        heteroaryl, or cycloalkyl;    -   R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆        alkoxy)(heterocyclyl), heterocyclyl, or R₂₃ and R₂₄ taken        together with the atoms to which they are attached join together        to form a heterocyclyl, heteroaryl, or cycloalkyl;    -   R₂₆ is hydrogen, heteroaryl, heterocyclyl, —N(R₁₃)(R₁₄), or        —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In certain aspects, the compounds of Formula (IV) have one of thefollowing Formulae (IV-D) and (IV-E):

-   -   or a pharmaceutically acceptable salt thereof.    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₆ is hydrogen, heteroaryl, heterocyclyl. —N(R₁₃)(R₁₄), or        —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In certain aspects, the compounds of Formula (IV) have one of thefollowing Formulae (IV-F) and (IV-G):

-   -   or a pharmaceutically acceptable salt thereof, wherein;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₂₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino;    -   s is 0, 1, or 2;    -   L₅ is CH₂, NH, S, or O;    -   L₆ is CH or N;    -   R₂₇ is hydrogen, —C(═O)R″, —S(═O)₂R₂₀;    -   R₂₈ is hydrogen. —C(═O)R″, —S(═O)₂R₂₀, or is absent if L₆ is O;        and    -   R²² is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —C(═O)N(R₁₃)(R₁₄), or        —N(R₁₃)(R₁₄).

In certain aspects of Formula (IV), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Formula (IV), R₁ is cyano.

In certain aspects of Formula (IV), R₂ is hydrogen or halo; R₂ ishydrogen.

In certain aspects of Formula (IV), R₃ is hydrogen.

In certain aspects of Formula (IV), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Formula (IV), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Formula (IV), R₂₅ is hydrogen.

In certain aspects of Formula (IV), L₂ is N.

In certain aspects of Formula (IV), L₁ is CH.

In certain aspects of Formula (IV), L₃ is CH.

In certain aspects of Formula (IV), L₄ is CH.

In certain aspects of Formula (IV), A is N.

In certain aspects of Formula (IV), A is CH.

In certain aspects of Formula (IV), R₂₆ is heterocyclyl.

In certain aspects of Formula (IV), R₂₄ is —N(R₁₃)(R₄).

In certain aspects of Formula (IV), L₅ and L₆ are each independently N.In certain aspects of Formula (IV), s is 1.

In certain aspects of Formula (IV), s is 0.

In certain aspects, the compounds of Formula (IV) have one of thefollowing Formulae (IV-H), (IV-I), (IV-J), (IV-K), (IV-L), (IV-M),(IV-N), or (IV-O):

-   -   or a pharmaceutically acceptable salt thereof.

Compounds of Formula (V)

In various aspects, the present disclosure provides for compounds ofFormula (V);

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   is N or O, wherein R₃₀ is absent if L₇ is O;    -   A is CH or NR    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1.2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₂₉ and R₃₀ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, —N(R₁₅R₁₆),        —C(═O)R₄₆, —R₄₈C(O)R₄₇, or R₂₉ and R₃₀ taken together with the        atoms to which they are attached join together to form a        heteroaryl or heterocyclyl, wherein R₃₀ is absent if L₇ is O;    -   R₄₆ and R₄₇ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₄₈ is alkyl or is absent;    -   R₃₁ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino; and    -   v is 0 or 1.

In certain aspects, the compounds of Formula (V) have one of thefollowing Formulae (V-A), (V-B), (V-C), or (V-D):

-   -   or a pharmaceutically acceptable salt thereof, wherein;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₁ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₀ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxyalkyl,        heteroaryl, heterocyclyl, —N(R₁₅R₁₆), —C(═O)R₄₆, or        —R₄₈C(═O)R₄₇, wherein R₃₀ is absent if L₇ is O;    -   R₄₆ and R₄₇ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₄₈ is alkyl or is absent;    -   R₃₁ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino;    -   L₈, L₉, and L₁₀ are each independently CH₂, NH, or O;    -   L₁₁ and L₁₂ are each independently CH or N;    -   R₃₂ and R₃₃ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, —S(═O)₂R₂₀, —C(═O)R₄, hydroxyalkyl, hydroxyl, or are        absent;    -   u is 0, 1, or 2; and    -   t is 0, 1, or 2.

In certain aspects of Formula (V), L₇ is N.

In certain aspects of Formula (V), L₇ is O.

In certain aspects of Formula (V), A is N.

In certain aspects of Formula (V), A is CH.

In certain aspects of Formula (V), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Formula (V), R₁ is cyano.

In certain aspects of Formula (V), R₂ is hydrogen or halo.

In certain aspects of Formula (V), R₂ is hydrogen.

In certain aspects of Formula (V), R₃ is fluorine.

In certain aspects of Formula (V), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Formula (V). R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Formula (V), R₃₁ is hydrogen.

In certain aspects of Formula (V), R₃₀ is hydrogen.

In certain aspects of Formula (V), L₈ is O.

In certain aspects of Formula (V), L₉ is O.

In certain aspects of Formula (V), L₁₀ is O and L₁₁ is N.

In certain aspects of Formula (V), L₁₂ is N.

In certain aspects of Formula (V), R₃₂ and R₃₃ are each independentlyhydrogen.

In certain aspects, the compounds of Formula (V) have one of thefollowing Formulae (V-I), (V-J), (V-K), (V-L), (V-M), (V-N), or (V-O):

-   -   or a pharmaceutically acceptable salt thereof.

Compounds of Formula (VI)

In certain aspects, the compounds of Formula (VI) have one of thefollowing Formulae (VI-A) or (VI-B):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L₁₃, L₁₄, L₁₅, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy. CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cycloalkyl, hydroxyl,        hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino. CF₃,        —OCF₃, —S(═O)₂R₂₀, or —N(R₁₅R₁₆);    -   R₃₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃₆ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₅R₁₆),        heterocyclyl, or heteroaryl;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino.

In certain aspects, the compounds of Formula (VI) have one of thefollowing Formulae (VI-C) or (VI-D):

-   -   or a pharmaceutically acceptable salt thereof, wherein;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₅ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₃₆ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R₁₅R₁₆),        heterocyclyl, or heteroaryl;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl,        hydroxyalkyl, or alkylamino; and    -   R₃₇ and R₃₈ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, hydroxyalkyl, heteroaryl, heterocyclyl, or R₃₇ and R₃₈        taken together with the atoms to which they are attached join        together to form a heteroaryl or heterocyclyl.

In certain aspects of Formula (VI), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Formula (VI), R₁ is cyano.

In certain aspects of Formula (VI), R₂ is hydrogen or halo.

In certain aspects of Formula (VI), R₂ is hydrogen.

In certain aspects of Formula (VI), R₃ is fluorine.

In certain aspects of Formula (VI), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Formula (VI), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Formula (VI), R₃₅ is hydrogen.

In certain aspects of Formula (VI). R₃₄ is heteroaryl;

In certain aspects of Formula (VI), R₃₄ is thienyl, pyrryl, furyl,pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl,imidazolyl, thiazolyl, pyranyl, tetrazolyl, pyrrolyl, pyrrolinyl,pyridazinyl, triazolyl, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl,thiadiazolyl, benzothiazolyl, or benzothiadiazolyl.

In certain aspects of Formula (VI), L₁₃ is N.

In certain aspects of Formula (VI), L₁₄ and L₁₅ are each independentlyCH.

In certain aspects of Formula (VI), A is N.

In certain aspects of Formula (VI), A is CH.

In certain aspects, the compounds of Formula (VI) have one of thefollowing Formulae (VI-E), (VI-F), (VI-G), (VI-H), or (VI-I):

-   -   or a pharmaceutically acceptable salt thereof.

In various aspects, the present disclosure provides for compounds ofFormula (VI-J):

-   -   or a pharmaceutically acceptable salt thereof, wherein:        -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,            —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)            wherein:            -   the C₃-C₅ cycloalkyl optionally includes an oxygen or                nitrogen heteroatom; and            -   when R¹ is not H, —CN or halogen, it is optionally                substituted with one or more halogens, each R² is                independently H, halogen or C₁-C₄ straight or branched                alkyl;        -   R³ is H, —OH, or halogen;        -   R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;        -   R²² is H, halogen, or C₁-C₂ alkyl;        -   R³⁵ is —C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹;            and        -   R³⁵¹ is C₁-C₆ straight or branched alkyl, cycloalkyl,            heterocyclyl, aryl or heteroaryl, each of which is            optionally substituted.

In some aspects of Formula (VI-J), R³ is H or halogen.

In some aspects of Formula (VI-J), R¹ is halogen, —CN or C₁-C₂haloalkyl.

In some aspects of Formula (VI-J), R²² is C₁-C₂ alkyl.

In some aspects of Formula (VI-J), R²¹ is cyclobutyl and R² is C₁-C₂alkyl.

In some aspects of Formula (VI-J), R²¹ is cyclobutyl.

In some aspects of Formula (VI-J), R³ is H or F.

In some aspects of Formula (VI-J), R¹ is —CN.

In some aspects of Formula (VI-J), R¹ is —CF₃.

In some aspects of Formula (VI-J), R²² is H, methyl or ethyl.

In some aspects of Formula (VI-J), R²² is H.

In some aspects of Formula (VI-J), R²² is methyl.

In some aspects of Formula (VI-J), R³⁵ is —C(O)—NHR³¹.

In some aspects of Formula (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Formula (VI-J), R³⁵¹ is(R)-(tetrahydrofuran-2-yl)methyl or (S)-(tetrahydrofuran-2-yl)methyl.

In some aspects of Formula (VI-J), R¹ is —CN, each R² is H, R¹ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—NHR³⁵¹ where R³⁵¹ isisopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Formula (VI-J), R³⁵ is —C(O)—O— R³⁵¹.

In some aspects of Formula (VI-J), R³⁵¹ is isopropyl, isobutyl,(R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Formula (VI-J), R¹ is —CN, each R² is H, R³ is H orF, R²¹ is C₃-C₄ cycloalkyl, R²² is H, R³⁵ is —C(O)—O—R³⁵¹ where R³⁵¹ isisopropyl, isobutyl, (R)-3-tetrahydrofuranyl, (S)-3-tetrahydrofuranyl,(R)-(tetrahydrofuran-2-yl)methyl, (S)-(tetrahydrofuran-2-yl)methyl,(R)-tetrahydro-2H-pyran-3-yl, or (S)-tetrahydro-2H-pyran-3-yl.

In some aspects of Formula (VI-J), R³⁵¹ is (R)-3-tetrahydrofuranyl or(S)-3-tetrahydrofuranyl.

In some aspects of Formula (VI-J), compounds have a Formula selectedfrom the group consisting of:

Compounds of Formula (VII) have one of the following Formulae (VII-A) or(VII-B):

-   -   or a pharmaceutically acceptable salt thereof wherein:    -   L₁₆ is C or N, wherein R₄₁ is absent if L₁₆ is N;    -   L₁₇, L₁₈, and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₄₀, R₄₂, and R₄₃ are each independently hydrogen, C₁₋₆ alkyl,        C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R, hydroxyalkyl, hydroxyl,        —N(R₁₃R₁₄), or R₄₁ and R₄₂ taken together with the atoms to        which they are attached join together to form a heteroaryl or        heterocyclyl;    -   R₄₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —S(═O)₂R₂₀, —C(═O)R,        hydroxyalkyl, hydroxyl, —N(R₁₃R₁₄), R₄₁ is absent if L₁₆ is N.        or R₄₁ and R₄₂ taken together with the atoms to which they are        attached join together to form a heteroaryl or heterocyclyl;    -   R is hydrogen, C₁₋₆ alkyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, hydroxyalkyl, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino.

In certain aspects of Formula (VII), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)N(R₁₃)(R₁₄).

In certain aspects of Formula (VII), R₁ is cyano.

In certain aspects of Formula (VII), R₂ is hydrogen or halo.

In certain aspects of Formula (VII), R₂ is hydrogen.

In certain aspects of Formula (VII). R₃ is hydrogen.

In certain aspects of Formula (VII), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Formula (VII), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Formula (VII), R₃₉ is hydrogen.

In certain aspects of Formula (VII). R₁₀ is hydrogen.

In certain aspects of Formula (VII), L₁₆ is N.

In certain aspects of Formula (VII), L₁₇ is N.

In certain aspects of Formula (VII), L₁₈ is CH.

In certain aspects of Formula (VII), L₁₈ is N.

In certain aspects of Formula (VII), A is N.

In certain aspects of Formula (VII), A is CH.

In certain aspects of Formula (VII). R₄₂ is C₁₋₆ alkyl.

In certain aspects of Formula (VII), R₄₁ is C₁₋₆ alkyl.

In certain aspects, the compounds of Formula (VII) have one of thefollowing Formulae (VII-C) or (VII-D):

-   -   or a pharmaceutically acceptable salt thereof.

Compounds of Formula (VIII)

In certain aspects, the compounds of Formula (VIII) have one of thefollowing Formulae (VIII-A), (VIII-B), or (VIII-C):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   L₁₉ and A are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(O)N(R₁₃)(R₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₃₉ is hydrogen, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₄₄ and R₄₅ are each independently hydrogen, C₁₋₆ alkyl, C₁₋₆        alkoxy, cycloalkyl, hydroxyalkl, aryl, heterocyclyl, heteroaryl,        alkylamino, —S(═O)₂R₂₀, —C(═O)R, or —N(R₁₃R₁₄); and    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀; and    -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino.

In certain aspects of Formula (VIII), R₁ is hydrogen, cyano, C₁₋₆ alkyl,C₁₋₆ alkoxy, or —C(═O)NN(R₁₃)(R₁₄).

In certain aspects of Formula (VIII), R₁ is cyano.

In certain aspects of Formula (VIII), R₂ is hydrogen or halo.

In certain aspects of Formula (VIII), R₂ is hydrogen.

In certain aspects of Formula (VIII), R₃ is hydrogen.

In certain aspects of Formula (VIII), R₂₁ and R₂₂ are each independentlyhydrogen or C₁₋₆ alkyl.

In certain aspects of Formula (VIII), R₂₁ and R₂₂ are each independentlyC₁₋₆ alkyl.

In certain aspects of Formula (VIII), R₃₉ is hydrogen.

In certain aspects of Formula (VIII), L₁₉ is N.

In certain aspects of Formula (VIII), A is N.

In certain aspects of Formula (VIII), A is CH.

In certain aspects, the compounds of Formula (VIII) have the followingFormula (VIII-D):

-   -   or a pharmaceutically acceptable salt thereof.

In various aspects, compounds of formula IX are provided:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl) or —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens,    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R¹ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄ alkyl)-OH,        -   —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or        -   —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl)            wherein:            -   t is 0 or 1;            -   the C₃-C₅ cycloalkyl optionally includes an oxygen or                nitrogen heteroatom:    -   L¹ is CR²³ or N;    -   L² is CH or N;    -   at least one of L¹ or L² is N; and    -   R²³ is H or C₁-C₄ straight or branched alkyl.

In some aspects of Formula (IX), R²⁴ is C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein tis 0 or 1.

In some aspects of Formula (IX), R²¹ is halogen, C₁-C₄ straight orbranched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionallyincludes an oxygen or nitrogen heteroatom, —S(O)_(u)—(C₁-C₄ straight orbranched alkyl) wherein u is 0 or 2, or —S(O)_(u)—(C₃-C₅ cycloalkyl)wherein u is 0 or 2:

In some aspects of Formula (IX), R³ is H or halogen.

In some aspects of Formula (IX), R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some aspects of Formula (IX), both L¹ and L² are N.

In some aspects of Formula (IX), R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyland R²² is C₁-C₂ alkyl.

In some aspects of Formula (IX), R²¹ is C₃-C₅ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Formula (IX), R²⁴ is —(C₁-C₂ alkyl)-O—(C₁-C₂ alkyl)wherein t is 0 or 1.

In some aspects of Formula (IX), R²¹ is C₃-C₅ cycloalkyl, R²² is C₁-C₂alkyl and R²⁴ is C₁-C₂ alkyl.

In some aspects of Formula (IX), R²¹ is cyclobutyl, R²² is C₁-C₂ alkyland R²⁴ is C₁-C₂ alkyl.

In some aspects of Formula (IX), R²¹ is cyclobutyl.

In some aspects of Formula (IX), R³ is H or F.

In some aspects of Formula (IX), R¹ is —CN.

In some aspects of Formula (IX), R¹ is —CF₃.

In some aspects of Formula (IX), R²² is H, methyl or ethyl.

In some aspects of Formula (IX), R²² is H.

In some aspects of Formula (IX), R²² is methyl.

In some aspects of Formula (IX), R¹ is —CN, each R² is hydrogen, R³ is Hor F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴is methyl, ethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl.

In some aspects of Formula (IX), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl. R²² is methyl. L¹ and L² are N, and R²⁴ ismethoxy or ethoxy.

In some aspects of Formula (IX), R¹ is —CN, each R² is H, R³ is H or F.R²¹ is C₃-C₄ cycloalkyl. R²² is methyl. L¹ is CH, L² is N. and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Formula (IX), R¹ is —CN, each R² is H, R¹ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is N, L² is CH, and R²⁴ ismethyl, ethyl, hydroxymethyl, methoxymethyl, or 2-methoxyethyl.

In some aspects of Formula (IX), compounds have a Formula selected fromthe group consisting of:

In various aspects, compounds of Formula (X) are provided:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:    -   the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen        heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R³ is H, —OH or halogen;    -   L³ is C(R⁶⁰)₂, O or NR⁵⁰;    -   each R⁶⁰ is independently H, —OH, —CN, —O_(t)—(C₃-C₅        cycloalkyl), —O—(C₁-C₄ straight or branched alkyl), or        —C(O)—N(R⁶⁰¹)₂ wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight or        branched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic        alkyl optionally containing an oxygen or nitrogen heteroatom,        —C(O)—N(R^(50′)1)₂, C₁-C₄ straight or branched alkyl wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom:    -   n is 1, 2 or 3;    -   m is 1 or 2;    -   R¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom    -   R²² is H, halogen, C₁-C₂ alkyl;    -   each R²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or        branched alkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl),        —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl),        —C(O)—O_(t)—(C₁-C₄ alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein:        -   t is 0 or 1, and        -   the C₃-C₅ cycloalkyl optionally includes an oxygen or            nitrogen heteroatom;    -   s is 0, 1 or 2;    -   each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or        branched alkyl; and    -   wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally join to        form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may        be two R²⁶, two R⁶⁰, two R⁵⁰, two R³⁰¹ or two R⁶⁰¹.

In some aspects of Formula (X), R²¹ is halogen, C₁-C₄ straight orbranched alkyl or C₃-C₅ cycloalkyl.

In some aspects of Formula (X), R³ is H or halogen.

In some aspects of Formula (X), R¹ is —CN or C₁-C₂ haloalkyl.

In some aspects of Formula (X), R³ is H or F.

In some aspects of Formula (X), R¹ is —CN.

In some aspects of Formula (X), R¹ is-CF₃.

In some aspects of Formula (X), n is 1.

In some aspects of Formula (X), n is 2.

In some aspects of Formula (X), m is 1

In some aspects of Formula (X), m is 2.

In some aspects of Formula (X), R²¹ is C₁-C₂ alkyl or C₃-C₅ cycloalkyland R²² is C₁-C₂ alkyl.

In some aspects of Formula (X), R²¹ is C₃-C₅ cycloalkyl and R²² is C₁-C₂alkyl.

In some aspects of Formula (X), n is 2, m is 1, L³ is —N—C(O)—O—(C₁-C₂alkyl).

In some aspects of Formula (X), L¹ is NR⁵⁰; R⁵⁰ is C₁-C₂ alkyl; R²¹ iscyclobutyl; R²² is H or methyl; R³ is H; R¹ is —CN; m is 2 and n is 1 or2.

In some aspects of Formula (X), n is 2, m is 1, L¹ is O and s is 0.

In some aspects of Formula (X), R²² is H, methyl or ethyl.

In some aspects of Formula (X), R²² is methyl.

In some aspects of Formula (X), R²² is H.

In some aspects of Formula (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, n is 2 and L¹ is NR⁵⁰ where R⁵⁰is methyl or ethyl.

In some aspects of Formula (X), R¹ is —CN, each R² is H, R³ is H or F,R²¹ is C₃-C₄ cycloalkyl. R²² is methyl, n is 2 and L³ is O.

In some aspects of Formula (X), the compound has a structure selectedfrom the group consisting of:

In various aspects, compounds of Formula (XI) are provided:

-   -   or a pharmaceutically acceptable salt thereof, wherein:        -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl.            —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)            wherein:            -   the C₃-C₅ cycloalkyl optionally includes an oxygen or                nitrogen heteroatom; and            -   when R¹ is not H, —CN or halogen, it is optionally                substituted with one or more halogens;        -   each R² is independently H, halogen or C₁-C₄ straight or            branched alkyl;        -   R³ is H, —OH, or halogen;        -   R²¹ is cyclobutyl, azetidin-1-yl, or cyclopropyl;        -   R²² is H, halogen, C₁-C₂ alkyl; and        -   R³⁵¹ is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl).

In some aspects of Formula (XI), R³ is H or halogen.

In some aspects of Formula (XI), R¹ is halogen, —CN or C₁-C₂ haloalkyl.

In some aspects of Formula (XI), R²¹ is C₃-C₄ cycloalkyl and R²² isC₁-C₂ alkyl.

In some aspects of Formula (XI), R²¹ is cyclobutyl and R²² is C₁-C₂alkyl.

In some aspects of Formula (XI), R²¹ is cyclobutyl.

In some aspects of Formula (XI), R³ is H or F.

In some aspects of Formula (XI), R¹ is —CN.

In some aspects of Formula (XI), R¹ is —CF₃.

In some aspects of Formula (XI), R²² is H, methyl or ethyl.

In some aspects of Formula (XI), R²² is H.

In some aspects of Formula (XI), R²² is methyl.

In some aspects of Formula (XI), R¹ is —CN, each R² is H, R¹ is H or F,R²¹ is cyclobutyl, R²² is methyl and R³⁵¹ is methyl or ethyl.

In some aspects of Formula (XI), the compound has a Formula selectedfrom the group consisting of:

In certain aspects, the present disclosure provides compounds having anyone of the structures found in Table 1. According to the presentdisclosure, the compounds of Table 1 are inhibitors of fatty acidsynthase.

Synthesis of Compounds

Also described herein are methods of synthesizing the compounds of thepresent disclosure. Compounds of the present disclosure can besynthesized as indicated in SYNTHETIC SCHEMES 1-13 below.

-   -   wherein:    -   R″ is hydrogen or alkyl;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;        -   q is 0, 1, 2, 3, or 4;        -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);        -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;        -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;        -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,            cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or            alkylamino; and        -   R₁₇ is hydrogen or alkyl.

-   -   wherein;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;        -   q is 0, 1, 2, 3, or 4;        -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);        -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;        -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy. CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;        -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,            cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or            alkylamino;    -   R₂₃ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, is        absent if L₁ is N, or R₂₃ and R₂₄ taken together with the atoms        to which they are attached join together to form a heterocyclyl,        heteroaryl, or cycloalkyl; and        -   R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy,            —(C₁₋₆ alkoxy)(heterocyclyl), heterocyclyl, or R₂₃ and R₂₄            taken together with the atoms to which they are attached            join together to form a heterocyclyl, heteroaryl, or            cycloalkyl.

-   -   wherein:    -   LG is a leaving group;    -   Nu is a nucleophile;    -   L₂, L₃, L₄, and L₄, are each independently CH or N;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀:        -   q is 0, 1, 2, 3, or 4;        -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);        -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;        -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;        -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,            cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or            alkylamino; and        -   R₁₇ is hydrogen or alkyl.

-   -   wherein;    -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;        -   q is 0, 1, 2, 3, or 4;        -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₄₋₆ alkoxy, or —N(R₁₃)(R₁₄);        -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl,        -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;        -   R₁₅ and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,            cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or            alkylamino;        -   R₁₇ is hydrogen or alkyl; and    -   R₂₄ is hydrogen, —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy, —(C₁₋₆        alkoxy)(heterocyclyl), or heterocyclyl.

wherein:

-   -   R₁ is hydrogen, cyano, halo, C₁₋₆ alkyl, C₁₋₆ alkoxy,        —C(═O)N(R₁₃)(R₁₄), —(CH₂)_(q)C(═O)N(R₁₃)(R₁₄), CF₃, —OCF₃, or        —S(═O)₂R₂₀;    -   q is 0, 1, 2, 3, or 4;    -   R₂₀ is hydrogen or C₁₋₆ alkyl, C₁₋₆ alkoxy, or —N(R₁₃)(R₁₄);    -   R₂ is hydrogen, halo, C₁₋₆ alkoxy, or C₁₋₆ alkyl;    -   R₃ is hydrogen, hydroxyl, halo, C₁₋₆ alkyl, or C₁₋₆ alkoxy;    -   R₂₁ and R₂₂ are each independently hydrogen, halo, cyano, C₁₋₆        alkyl, C₁₋₆ alkoxy, CF₃, —OCF₃, or —S(═O)₂R₂₀;    -   R₁₃ and R₁₄ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl,        alkylamino, —N(R₁₅R₁₆), or —S(═O)₂R₂₀;    -   R₁, and R₁₆ are each independently hydrogen, C₁₋₆ alkyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, hydroxyalkyl, or        alkylamino;    -   R₁₇ is hydrogen or alkyl;    -   R₂₄ is hydrogen. —N(R₁₃)(R₁₄), C₁₋₆ alkyl, C₁₋₆ alkoxy. —(C₁₋₆        alkoxy)(heterocyclyl), or heterocyclyl;    -   R₂₉ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, hydroxyalkyl,        heteroaryl, heterocyclyl, —N(R₁₅R₁₆), —C(═O)R₄₆, or        —R₄₈C(═O)R₄₇;    -   R₃₄ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, cycloalkyl, hydroxyl,        hydroxyalkyl, aryl, heterocyclyl, heteroaryl, alkylamino, CF₃,        —OCF₃, —S(═O)₂R₂₀, or —N(R₁₅R₁₆); and    -   m 0, 1, or 2.

Schemes 6-13 provides a synthesis for exemplary compounds of formula IXwherein:

-   -   R¹ is H, —CN, halogen, C₁-C₄ straight or branched alkyl,        —O—(C₃-C₅ cycloalkyl), —O—(C₁-C₄ straight or branched alkyl)        wherein:        -   C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen            heteroatom; and        -   when R¹ is not H, —CN or halogen, it is optionally            substituted with one or more halogens;    -   each R² is independently hydrogen, halogen or C₁-C₄ straight or        branched alkyl;    -   R¹ is H, —OH, or halogen;    -   R²¹ is H, halogen, C₁-C₄ straight or branched alkyl, C₃-C₅        cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includes an        oxygen or nitrogen heteroatom;    -   R²² is H, halogen, or C₁-C₂ alkyl;    -   R²³ is H or C₁-C₄ straight or branched alkyl; and    -   R²⁴ is H, C₁-C₄ straight or branched alkyl, —(C₁-C₄        alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)-(C₃-C₅ cycloalkyl), or        —(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein:        -   t is 0 or 1; and    -   the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogen        heteroatom.

Additional methods for producing particular compounds according to thepresent disclosure are provided in the EXAMPLES. One skilled in the artwill recognize that other compounds of the Formulae disclosed can bemade by modifications to the specifically disclosed schemes employingmethods known to those of skill in the art. Additional examples can befound in Table 1.

Many such techniques are well known in the art. However, many of theknown techniques are elaborated in Compendium of Organic SyntheticMethods (Vol. 1, 1971; Vol. 2, 1974; Vol. 3, 1977; Vol. 4, 1980; Vol. 5,1984; and Vol. 6 as well as March in Advanced Organic Chemistry (1985);Comprehensive Organic Synthesis. Selectivity. Strategy & Efficiency inModern Organic Chemistry. In 9 Volumes (1993); Advanced OrganicChemistry Part B: Reactions and Synthesis, Second Edition (1983);Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, SecondEdition (1977); Protecting Groups in Organic Synthesis, Second Edition;and Comprehensive Organic Transformations (1999).

Viral Infection Pathways

The host cell targets inhibited by the present compounds and methodsplay a role in the viral replication and/or infection pathways.Targeting of such host cell targets modulates the replication and/orinfection pathways of the viruses. In preferred aspects the identifiedhost cell targets are directly or indirectly modulated using thecompositions of the present disclosure. The modulation of such host celltargets can also be performed by targeting entities in the upstream ordownstream signaling pathways of the host cell targets.

According to the present disclosure, viral infection can be treated bytargeting the fatty acid synthesis pathway, and in particular fatty acidsynthase. HRV is representative of viruses that can be treated accordingto the present disclosure. Like other viruses, the replication of HRVinvolves six phases, transmission, entry, replication, biosynthesis,assembly, and exit. Entry occurs by endocvtosis, replication and vRNPassembly takes place in the nucleus, and the virus buds from the plasmamembrane. In the infected patient, the virus targets airway epithelialcells. The present compounds and methods target and modulate at leastone host cell targets involved in such pathways.

For some viruses a great deal of progress has been made in theelucidation of the steps involved during infection of host cells. Forexample, experiments initiated in the early 1980s showed that influenzavirus follows a stepwise, endocytic entry program with elements sharedwith other viruses such as alpha- and rhabdoviruses (Marsh and Helenius1989; Whittaker 2006). The steps include: 1) Initial attachment tosialic acid containing glycoconjugates receptors on the cell surface; 2)signaling induced by the virus particle; 3) endocytosis byclathrin-dependent and clathrin-independent cellular mechanism; 4)acid-induced, hemaglutinin (HA)-mediated penetration from lateendosomes; 5) acid-activated, M2 and matrix protein (M1) dependentuncoating of the capsid; and, 6) intra-cytosolic transport and nuclearimport of vRNPs. These steps depend on assistance from the host cell inthe form of sorting receptors, vesicle formation machinery,kinase-mediated regulation, organelle acidification, and, most likely,activities of the cytoskeleton.

Influenza attachment to the cells surface occurs via binding of the HA 1subunit to cell surface glycoproteins and glycolipids that carryoligosaccharide moieties with terminal sialic acid residues (Skehel andWiley 2000). The linkage by which the sialic acid is connected to thenext saccharide contributes to species specificity. Avian strainsincluding H5N1 prefer an a-(2,3)-link and human strains a-(2,6)-link(Matrosovich 2006). In epithelial cells, binding occurs preferentiallyto microvilli on the apical surface, and endocytosis occurs at base ofthese extensions (Matlin 1982). Whether receptor binding induces signalsthat prepare the cell for the invasion is not yet known, but it islikely because activation of protein kinase C and synthesis ofphopshatidylinositol-3-phosphate (PI3P) are required for efficient entry(Sieczkarski et al. 2003; Whittaker 2006).

Endocytic internalization occurs within a few minutes after binding(Matlin 1982; Yoshimura and Ohnishi 1984). In tissue culture cellsinfluenza virus makes use of three different types of cellularprocesses; 1) preexisting clathrin coated pits, 2) virus-inducedclathrin coated pits, and 3) endocytosis in vesicles without visiblecoat (Matlin 1982; Sieczkarski and Whittaker 2002; Rust et al. 2004).Video microscopy using fluorescent viruses showed the virus particlesundergoing actin-mediated rapid motion in the cell periphery followed byminus end-directed, microtubule-mediated transport to the perinucleararea of the cell. Live cell imaging indicated that the virus particlesfirst entered a subpopulation of mobile, peripheral early endosomes thatcarry them deeper into the cytoplasm before penetration takes place(Lakadamyali et al. 2003; Rust et al. 2004). The endocytic process isregulated by protein and lipid kinases, the proteasome, as well as byRabs and ubiquitin-dependent sorting factors (Khor et al. 2003;Whittaker 2006).

The membrane penetration step is mediated by low pH-mediated activationof the trimeric, metastable HA, and the conversion of this Type I viralfusion protein to a membrane fusion competent conformation (Maeda et al.1981; White et al. 1982). This occurs about 16 min afterinternalization, and the pH threshold varies between strains in the5.0-5.6 range. The target membrane is the limiting membrane ofintermediate or late endosomes. The mechanism of fusion has beenextensively studied (Kielian and Rey 2006). Further it was observed thatfusion itself does not seem to require any host cell components except alipid bilayer membrane and a functional acidification system (Maeda etal. 1981; White et al. 1982). The penetration step is inhibited byagents such as lysosomotropic weak bases, carboxylic ionophores, andproton pump inhibitors (Matlin 1982; Whittaker 2006).

To allow nuclear import of the incoming vRNPs, the capsid has to bedisassembled. This step involves acidification of the viral interiorthrough the amantadine-sensitive M2-channels causes dissociation of M1from the vRNPs (Bukrinskaya et al. 1982; Martin and Helenius 1991; Pintoet al. 1992). Transport of the individual vRNPs to the nuclear porecomplexes and transfer into the nucleus depends on cellular nucleartransport receptors (O'Neill et al. 1995; Cros et al. 2005). Replicationof the viral RNAs (synthesis of positive and negative strands), andtranscription occurs in complexes tightly associated with the chromatinin the nucleus. It is evident that, although many of the steps arecatalyzed by the viral polymerase, cellular factors are involvedincluding RNA polymerase activating factors, a chaperone HSP90, hCLE,and a human splicing factor UAP56. Viral gene expression is subject tocomplex cellular control at the transcriptional level, a control systemdependent on cellular kinases (Whittaker 2006).

The final assembly of an influenza particle occurs during a buddingprocess at the plasma membrane. In epithelial cells, budding occurs atthe apical membrane domain only (Rodriguez-Boulan 1983). First, theprogeny vRNPs are transported within the nucleoplasm to the nuclearenvelope, then from the nucleus to the cytoplasm, and finally theyaccumulate in the cell periphery. Exit from the nucleus is dependent onviral protein NEP and M1, and a variety of cellular proteins includingCRM1 (a nuclear export receptor), caspases, and possibly some nuclearprotein chaperones. Phosphorylation plays a role in nuclear export byregulating M1 and NEP synthesis, and also through the MAPK/ERK system(Bui et al. 1996; Ludwig 2006). G protein and protein kinase signalingis involved in influenza virus budding from infected host cells (Hui E.and Navak D, 2002).

The three membrane proteins of the virus are synthesized, folded andassembled into oligomers in the ER (Doms et al. 1993). They pass throughthe Golgi complex; undergo maturation through modification of theircarbohydrate moieties and proteolytic cleavage. After reaching theplasma membrane they associate with M1 and the vRNPs in a buddingprocess that results in the inclusion of all eight vRNPs and exclusionof most host cell components except lipids.

Influenza infection is associated with activation of several signalingcascades including the MAPK pathway (ERK, JNK, p38 and BMK-1/ERK5), theIkB/NF-kB signaling module, the Raf/MEK/ERK cascade, and programmed celldeath (Ludwig 2006). These result in a variety of effects that limit theprogress of infection such as transcriptional activation of IFNb,apoptotic cell death, and a block in virus escape of from late endosomes(Ludwig 2006).

Most previous studies on virus-cell interactions were performed intissue culture using tissue culture- or egg-adapted virus strains. Theviruses in these examples were adapted in such a manner that changeswere induced that affected receptor binding and tropism (Matrosovich2006). Infection with wild-type pathogenic strains is provides a morenatural picture of viral interaction with host proteins. It is knownthat in the human airways influenza A and B primarily infect nonciliated epithelial cells in the upper respiratory track carrying NeuSAca-(2,6)-Gal, whereas avian strains infect ciliated epithelial cell witha-(2,3)-linked sialic acids deeper in the airways (Matrosovich et al.2004a).

Additionally, progress has been made in the elucidation of the stepsinvolved during infection by HRV of host cells. Selected events inrhinovirus infection of the normal human airway can be regarded asoccurring sequentially. Initial steps in rhinovirus pathogenesis arebelieved to include viral entry through the nose, mucociliary transportof virus to the posterior pharynx, and initiation of infection inciliated and non-ciliated epithelial cells of the upper airway. Viralreplication peaks on average within 48 h of initiation of infection andpersists for up to 3 wk. Infection is followed by activation of severalinflammatory mechanisms, which can include release or generation ofinterleukins, bradykinins, prostaglandins, and possibly histamine andstimulation of parasympathetic reflexes. Pathophysiologic processes areinitiated, which include vasodilatation of nasal blood vessels,transudation of plasma, glandular secretion, and stimulation of nervefibers, causing pain and triggering sneeze and cough reflexes. Theresultant clinical illness is a rhinosinusitis, pharyngitis, andbronchitis, which, on average, lasts one week.

Changes in gene expression profiles during in vivo rhinovirus infectionshave been identified (Proud, D., et al., Am. J. Respir. Crt. Care Med.Vol 178. pp 962-968, 2008). Nasal epithelial scrapings were obtainedbefore and during experimental rhinovirus infection, and gene expressionwas evaluated by microarray. Viperin is identified as an antiviralprotein induced by interferon (IFN), viral infections, andpathogen-associated molecules. Naturally acquired rhinovirus infections,cultured human epithelial cells, and short interfering RNA knockdownwere used to further evaluate the role of viperin in rhinovirusinfections. Symptom scores and viral titers were measured in subjectsinoculated with rhinovirus or a sham control, and changes in geneexpression were assessed 8 and 48 hours after inoculation.Rhinovirus-induced changes in gene expression were not observed 8 hoursafter viral infection, but 11,887 gene transcripts were significantlyaltered in scrapings obtained 2 days post-inoculation. Major groups ofup-regulated genes include chemokines, signaling molecules,interferon-responsive genes, and antivirals. Rhinovirus infectionsignificantly alters the expression of many genes associated with theimmune response, including chemokines and antivirals. Some of the genesmarkedly induced by HRV-16 infection include but are not limited toCCL2, CCL8, CXCL11, CXCL10, CXCL13, CXCL9, CCL20, IFIT2, GBP1, IFIT1,GIP2, IFIT4, IL28B, IRF7, CIG5, NOS2A, OAS3, OASL, OAS2, OAS1, MX2, MX1,PLSCR1, SOCS1, SOCS2, MDA5, RIGI, SOCS3, ICAM-1, HAPLN3, MMP12, EPSTI1,and TNC.

Fatty Acid Synthesis Pathway

Various aspects of the present disclosure relate to compositions andmethods that modulate the activity of the fatty acid synthesis pathwayto treat a viral infection or treat cancer. The fatty acid synthesispathway in humans can use four enzymes: 1) acetyl-CoA carboxylase (ACC),which can synthesize malonyl-CoA; 2) malic enzyme, which can produceNADPH; 3) citrate lyase, which can synthesize acetyl-CoA; and 4) fattyacid synthase, which can catalyze NADPH-dependent synthesis of fattyacids from acetyl-CoA and malonyl-CoA. In various aspects, the presentdisclosure relates to treatment of viral infections and cancer bymodulating the activity of the fatty acid synthase protein.

The final products of fatty acid synthase are free fatty acids which canuse separate enzymatic derivatization with coenzyme-A for incorporationinto other products. In humans, fatty acid synthesis can occur in twosites: the liver, where palmitic acid can be made (Roncari, (1974) Can.J. Biochem., 52:221-230) and lactating mammary gland, where C₁₀-C₁₄fatty acids can be made (Thompson, et al., (1985) Pediatr. Res.,19:139-143).

Fatty acids can be synthesized in the cytoplasm from acetyl-CoA.Acetyl-CoA can be generated from pyruvate by pyruvate dehydrogenase(PDH) and by β-oxidation of fatty acids in the mitochondria. A “citrateshuttle” can transport acetyl-CoA from the mitochondria to thecytoplasm. Acetyl-CoA can react with oxaloacetate to yield citrate, anda tricarboxylate translocase can transport citrate from the mitochondriato the cytosol. In the cytoplasm, citrate can be cleaved back tooxaloacetate and acetyl-CoA, a reaction that can be catalyzed byATP-citrate lyase. Oxaloacetate can be converted back to pyruvate forre-entry into mitochondria.

Acetyl-CoA can be converted to malonyl-CoA. Acetyl-CoA carboxylase (ACC)is a complex multifunctional, biotin-containing, enzyme system that cancatalyze carboxylation of acetyl-CoA to malonyl-CoA. This conversion isan irreversible, rate-limiting step in fatty acid synthesis. ACC cancarry out three functions: biotin carboxyl carrier protein, biotincarboxylase and carboxyltransferase. ATP-dependent carboxylation ofbiotin, a prosthetic group (cofactor) can be followed by transfer of thecarboxyl group to acetyl-CoA.

HCO₃ ⁻+ATP+acetyl-CoA→ADP+P₁+malonyl-CoA

There are two ACC forms, alpha and beta, encoded by two different genesACC-alpha (also known as ACC, ACAC, ACC1, ACCA, and ACACA) can encodeprotein highly enriched in lipogenic tissues. Multiple alternativelyspliced transcript variants divergent in the sequence and encodingdistinct isoforms have been found for this gene. ACC-beta (also known asACC2, ACCB, HACC275, and ACACB) can encode protein thought to controlfatty acid oxidation by means of the ability of malonyl-CoA to inhibitcarnitine-palmitoyl-CoA transferase I, the rate-limiting step in fattyacid uptake and oxidation by mitochondria. ACC-beta may be involved inthe regulation of fatty acid oxidation, rather than fatty acidbiosynthesis. There is evidence for the presence of two ACC-betaisoforms.

ACC can be regulated by the phosphorylation/dephosphorylation oftargeted serine residues. For example, AMP-activated kinase (AMPK) canphosphorylate ACC, and this phosphorylation can inhibit the ability ofACC to produce malonyl-CoA. On ACACA, AMPK can phosphorylate Ser79,Ser1200, and Ser1215 (Park, S. H., et al., (2002) J. Appl. Physiol.92:2475-82). AMPK can phosphorylate Ser218 on ACACB (Hardie, D. G.(1992) Biochim. Biophys. Acta 1123:231-8). Also, cAMP-dependent proteinkinase (Protein Kinase A, or PKA) can phosphorylate ACC.

ACC can be regulated by allosteric transformation by citrate orpalmitoyl-CoA. For example, citrate can be a positive effector (i.e.citrate can allosterically activate ACC). Citrate concentration can behigh when there is adequate acetyl-CoA entering the Krebs Cycle. Excessacetyl-CoA can then be converted via malonyl-CoA to fatty acids.Palmitoyl-CoA can be a negative effector. Palmitoyl-CoA, which is theproduct of Fatty Acid Synthase (FASN), can promote the inactiveconformation of ACC, which can reduce production of malonyl-CoA (afeedback inhibition process). AMP can regulate fatty acid synthesis byregulating the availability of malonyl-CoA. Insulin binding a receptorcan activate a phosphatase to dephosphorylate ACC, which can remove theinhibitory effect.

The fatty acid synthase gene (also known as FAS, OA-519, SDR27X1;MGC14367; MGC15706. FASN) is involved in fatty acid synthesis. Theenzyme encoded by this gene is a multifunctional protein ofapproximately 272 kDa with multiple domains, each with distinct enzymeactivities that can play a role in fatty acid biosynthesis. FASN cancatalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA, inthe presence of NADPH, into long-chain saturated fatty acids. In somecancer cell lines, FASN protein has been found to be fused with estrogenreceptor-alpha (ER-alpha), in which the N-terminus of FASN is fusedin-frame with the C-terminus of ER-alpha.

FASN protein can exist in the cytosol as a dimer of identical subunits.FASN consists of three catalytic domains in the N-terminal section(-ketoacyl synthase (KS), malonyl/acetyltransferase (MAT), and dehydrase(DH)). The N-terminal section is separated by a core region of about 600amino acids from four C-terminal domains (enoyl reductase (ER),-ketoacyl reductase (KR), acyl carrier protein (ACP), and thioesterase(TE)). The crystal structure of a mammalian fatty acid synthase has beenreported (Maier, T., et al., (2008) Science 321: 1315-1322). Each of thecatalytic domains of FASN can be targeted in the methods of treatingviral infection of the provided invention.

The enzymatic steps of fatty acid synthesis can involve decarboxylativecondensation, reduction, dehydration, and another reduction and canresult in a saturated acyl moiety. NADPH can be an electron donor inreductive reactions.

Antiviral Activity

In various aspects, the present disclosure provides methods for treatingviral infection in a subject, the method comprising administering to asubject in need of such treatment an effective amount of a compound ofFormulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI) or as provided in Table 1.

In various aspects, the disclosure provides methods for treating a viralinfection, the method comprising administering the compounds of thepresent disclosure to a subject in need thereof the agent.

The present disclosure contemplates the treatment of any viral infectionthat targets the fatty acid synthesis pathway in a host, and inparticular by modulating the activity of fatty acid synthase. Forexample, the present methods can be used to treat influenza infection,adenovirus infection, respiratory syncytial virus infection, poxvirusinfection, poliomyelitis infection, hepatitis C infection, yellow feverinfection, dengue fever infection, rhinovirus infection, and the like.

In various aspects, the present disclosure provides methods for treatinghepatitis C infection by administering to the subject one or morecompounds disclosed herein. In modulating the FASN pathway in thesubject, hepatitis C infection is treated. It has been shown thatexpression of FASN is upregulated in human hepatoma cell line Huh7 whenthese cells are infected with HCV. Inhibiting FASN production with aFASN inhibitor reduced the production of HCV. Thus administration to asubject of the compounds of the present disclosure. (Yang. W., et al.,(2008) Hepatology 48(5): 1396-1403). It is demonstrated in the EXAMPLESthat FASN inhibition correlates to inhibition of HCV.

In certain aspects, the methods of inhibiting viral infection can beperformed in vitro. In further aspects, the methods of inhibiting viralinfection can be performed in vivo.

In certain aspects the compounds of the present disclosure may be usedin combination with other antiviral treatments in the treating of viralinfection.

In various aspects, the viral infection is a human yellow feverinfection. In further aspects, the viral infection is a human hepatitisC infection. In yet further aspects, the viral infection is a humanrhinoviral infection.

In various aspects the compounds of the present disclosure can be usedfor the treatment of infection of an animal subject, such as a human, byany of a plethora of viruses.

In certain aspects, the compounds of the present disclosure can be usedfor the inhibition of a host by a respiratory virus. Respiratory virusesare most commonly transmitted by airborne droplets or nasal secretionsand can lead to a wide spectrum of illness. Respiratory viruses includethe respiratory syncytial virus (RSV), influenza viruses, coronavirusessuch as SARS, adenoviruses, parainfluenza viruses and rhinoviruses(HRV).

According to one aspect, the present disclosure can be used to treatinfection by HRV. The genus of rhinoviruses is a member of thePicornaviridae family of viruses. Genera within the family include theGenus Enterovirus. Rhminovirus, Cardiovirus, Aphthovirus, Hepatovinrus,Parechovirus, Erbovirus, Kobuvirus, Teschovirus. Human rhinoviruses(HRV) include the most common viruses that infect humans and can causethe common cold. HRV are lytic in nature. Rhinoviruses havesingle-stranded positive sense RNA genomes of between 7.2 and 8.5 kb inlength. At the 5′ end of these genomes is a virus-encoded protein, andlike mammalian mRNA, there is also a 3′ poly-A tail. The 5′-terminal UMPof the viral RNA is covalently linked to the small viral protein VPg(Paul, A. V., et al., Nature 1998, 393(6682):280-284). The 5′UTRcontains two structural elements. One is the 5′-cloverleaf structureinvolved in the plus-strand RNA synthesis and in the process ofswitching from translation to replication (Huang, H., et al.,Biochemistry 2001, 40(27):8055-8064). The other is the internalribosomal entry site (IRES) which promotes translation of thepolyprotein. In addition, species-specific internal cis-actingreplication elements (cre) have been identified in human enteroviruses(HEV), HRV-A and HRV-B (Gerber, K., Wimmer, E., Paul, A. V., J. Virol.2001, 75(22):10979-10990). The viral particles themselves are notenveloped and are icosahedral in structure. Rhinoviruses also grow bestin temperatures between 33-35° C. They are also sensitive to acidicenvironment.

HRV viral proteins are transcribed as a single long polypeptide, whichis cleaved into the viral structural and nonstructural proteins.Rhinoviruses are composed of a capsid that contains four viral proteinsVP1, VP2, VP3 and VP4 (Rossmann, M., et al. 1985 Nature 317 (6033);145-53; Smith, T., et al. 1986, Science 233 (4770): 1286-93). Theisometric nucleocapsids are 22-40 nm in diameter. VP1, VP2, and VP3 formthe major part of the protein capsid. The much smaller VP4 protein has amore extended structure and lies at interface between the capsid and theRNA genome. There are 60 copies of each of these proteins assembled asan icosahedron. Human antibodies that target epitopes lying on theexterior regions of VP1-VP3 play a role in the immune response to HRVs.

HRVs have two general modes of transmission: 1) via aerosols ofrespiratory droplets and 2) from contaminated surfaces, including directperson-to-person contact. The primary route of entry for rhinoviruses isthe upper respiratory tract. Afterwards, an HRV binds to ICAM-1(Inter-Cellular Adhesion Molecule 1) also known as CD54 (Cluster ofDifferentiation 54) receptors on respiratory epithelial cells. As thevirus replicates and spreads, infected cells release chemokines andcytokines, which in turn activate inflammatory mediators. Infectionoccurs rapidly, with the rhinovirus adhering to surface receptors within15 minutes of entering the respiratory tract. The incubation period isgenerally 8-10 hours before symptoms begin to occur. HRVs are the mostfrequent cause of infection across all age groups of the humanpopulation. Replication is often restricted to the upper respiratorytract leading to self-limited illnesses such as the common cold.However, HRV infections can also exacerbate pre-existing airwaydisorders, invade the lower respiratory tract and lead to seriouscomplications.

In another aspect, the compounds of the present disclosure can be usedfor the treatment of infection by the influenza virus by targeting thepathways that the virus relies on for infection or replication.Influenza viruses belong to Orthomyxoviridae family of viruses. Thisfamily also includes Thogoto viruses and Dhoriviruses. There are severaltypes and subtypes of influenza viruses known, which infect humans andother species. Influenza type A viruses infect people, birds, pigs,horses, seals and other animals, but wild birds are the natural hostsfor these viruses. Influenza type A viruses are divided into subtypesand named on the basis of two proteins on the surface of the virus:hemagglutinin (HA) and neuraminidase (NA). For example, an “H7N2 virus”designates an influenza A subtype that has an HA 7 protein and an NA 2protein. Similarly an “H5N1” virus has an HA 5 protein and an NA 1protein. There are 16 known HA subtypes and 9 known NA subtypes. Manydifferent combinations of HA and NA proteins are possible. Only someinfluenza A subtypes (i.e., HIN1, HIN2, and H3N2) are currently ingeneral circulation among people. Other subtypes are found most commonlyin other animal species. For example, H7N7 and H3N8 viruses causeillness in horses, and H3N8 also has recently been shown to causeillness in dogs (see www.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Antiviral agents which target host cell proteins involved in influenzainfection can be used to protect high-risk groups (hospital units,institutes caring for elderly, immuno-suppressed individuals), and on acase by case basis. A potential use for antiviral agents is to limit thespread and severity of the future pandemics whether caused by avian H5N1or other strains of influenza virus. Avian influenza A viruses of thesubtypes H5 and H7, including H5N1, H7N7, and H7N3 viruses, have beenassociated with high pathogenicity, and human infection with theseviruses have ranged from mild (H7N3, H7N7) to severe and fatal disease(H7N7, H5N1). Human illness due to infection with low pathogenicityviruses has been documented, including very mild symptoms (i.e.,conjunctivitis) to influenza-like illness. Examples of low pathogenicityviruses that have infected humans include H7N7, H9N2, and H7N2 (seewww.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza B viruses are usually found in humans but can also infectseals. Unlike influenza A viruses, these viruses are not classifiedaccording to subtype. Influenza B viruses can cause morbidity andmortality among humans, but in general are associated with less severeepidemics than influenza A viruses. Although influenza type B virusescan cause human epidemics, they have not caused pandemics. (seewww.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza type C viruses cause mild illness in humans and do not causeepidemics or pandemics. These viruses can also infect dogs and pigs.These viruses are not classified according to subtype. (seewww.cdc.gov/flu/avian/gen-info/flu-viruses.htm).

Influenza viruses differ from each other in respect to cell surfacereceptor specificity and cell tropism, however they use common entrypathways. The compounds of the present disclosure advantageously targetpathways that are common to multiple viruses giving rise to broaderantiviral activity. Thus, the present compounds can also prove usefulagainst unrelated viruses that use similar pathways. For example, theagents can protect airway epithelial cells against a number of differentviruses in addition to influenza viruses.

In certain aspects, the compounds of the present disclosure can be usedfor the treatment of infection by adenoviruses. Most adenovirusescommonly cause respiratory illness; symptoms of respiratory illnesscaused by adenovirus infection range from the common cold syndrome topneumonia, croup, and bronchitis. Patients with compromised immunesystems are especially susceptible to severe complications of adenovirusinfection. Acute respiratory disease (ARD), first recognized amongmilitary recruits during World War II, can be caused by adenovirusinfections during conditions of crowding and stress. Adenoviruses aremedium-sized (90-100 nm), nonenveloped icosohedral viruses containingdouble-stranded DNA. There are 49 immunologically distinct types (6subgenera: A through F) that can cause human infections. Adenovirusesare unusually stable to chemical or physical agents and adverse pHconditions, allowing for prolonged survival outside of the body. Someadenoviruses, such as AD2 and Ad5 (species C) use clathrin mediatedendocvtosis and macropinocytosis for infectious entry. Otheradenoviruses, such as Ad3 (species B) use dynamin dependent endocytosisand macropinocytosis for infectious entry.

In certain aspects, the compounds of the present disclosure can be usedfor the treatment of infection by respiratory syncytial virus (RSV). RSVis the most common cause of bronchiolitis and pneumonia among infantsand children under 1 year of age. Illness begins most frequently withfever, runny nose, cough, and sometimes wheezing. During their first RSVinfection, between 25% and 40% of infants and young children have signsor symptoms of bronchiolitis or pneumonia, and 0.5% to 2% requirehospitalization. Most children recover from illness in 8 to 15 days. Themajority of children hospitalized for RSV infection are under 6 monthsof age. RSV also causes repeated infections throughout life, usuallyassociated with moderate-to-severe cold-like symptoms; however, severelower respiratory tract disease can occur at any age, especially amongthe elderly or among those with compromised cardiac, pulmonary, orimmune systems. RSV is a negative-sense, enveloped RNA virus. The virionis variable in shape and size (average diameter of between 120 and 300nm), is unstable in the environment (surviving only a few hours onenvironmental surfaces), and is readily inactivated with soap and waterand disinfectants.

In certain aspects, the compounds of the present disclosure can be usedfor the treatment of infection by human parainfluenza virus (HPIV).HPIVs are second to respiratory syncytial virus (RSV) as a common causeof lower respiratory tract disease in young children. Similar to RSV,HPIVs can cause repeated infections throughout life, usually manifestedby an upper respiratory tract illness (i.e., a cold and/or sore throat).HPIVs can also cause serious lower respiratory tract disease with repeatinfection (i.e., pneumonia, bronchitis, and bronchiolitis), especiallyamong the elderly, and among patients with compromised immune systems.Each of the four HPIVs has different clinical and epidemiologicfeatures. The most distinctive clinical feature of HPIV-1 and HPIV-2 iscroup (i.e., laryngotracheobronchitis); HPIV-1 is the leading cause ofcroup in children, whereas HPIV-2 is less frequently detected. BothHPIV-1 and -2 can cause other upper and lower respiratory tractillnesses. HPIV-3 is more often associated with bronchiolitis andpneumonia. HPIV-4 is infrequently detected, possibly because it is lesslikely to cause severe disease. The incubation period for HPIVs isgenerally from 1 to 7 days. HPIVs are negative-sense, single-strandedRNA viruses that possess fusion and hemagglutinin-neuraminidaseglycoprotein “spikes” on their surface. There are four serotypes typesof HPIV (1 through 4) and two subtypes (4a and 4b). The virion varies insize (average diameter between 150 and 300 nm) and shape, is unstable inthe environment (surviving a few hours on environmental surfaces), andis readily inactivated with soap and water.

In various aspects, the compounds of the present disclosure can be usedfor the treatment of infection by coronavirus. Coronavirus is a genus ofanimal virus belonging to the family Coronaviridae. Coronaviruses areenveloped viruses with a positive-sense single-stranded RNA genome and ahelical symmetry. The genomic size of coronaviruses ranges fromapproximately 16 to 31 kilobases, extraordinarily large for an RNAvirus. The name “coronavirus” is derived from the Latin corona, meaningcrown, as the virus envelope appears under electron microscopy to becrowned by a characteristic ring of small bulbous structures. Thismorphology is actually formed by the viral spike peplomers, which areproteins that populate the surface of the virus and determine hosttropism. Coronaviruses are grouped in the order Nidovirales, named forthe Latin nidus, meaning nest, as all viruses in this order produce a 3′co-terminal nested set of subgenomic mRNA's during infection. Proteinsthat contribute to the overall structure of all coronaviruses are thespike, envelope, membrane and nucleocapsid. In the specific case of SARSa defined receptor-binding domain on S mediates the attachment of thevirus to its cellular receptor, angiotensin-converting enzyme 2.

In a further embodiment, the disease state associated with dysregulationof the mTOR pathway is a viral infection. In one embodiment, the viralinfection is by a virus from the herpesviridae family of viruses. In oneembodiment the viral infection is by a herpesviridae virus selected fromthe group consisting of herpes simplex virus (HSV) types 1 and 2,varicella-zoster virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV),human herpesvirus 6 (variants A and B), human herpesvirus 7, humanherpesvirus 8 (Kaposi's sarcoma—associated herpesvirus, KSHV), andcercopithecine herpesvirus 1 (B virus). In one embodiment the viralinfection is by a virus selected from human cytomegalovirus and herpessimplex virus-1.

In one embodiment, the viral infection is by a virus from theparamyxoviridae family of viruses. In one embodiment, the viralinfection is by a paramyxoviridae virus selected from the groupconsisting of Respiratory syncytial virus (RSV), mumps, measles, humanparainfluenza viruses such as Parainfluenza Virus Type 3 (PIV3), Humanmetapneumovirus, Hendra virus (HeV), Nipah virus (NiV), and Cedar Virus.

In one embodiment, the viral infection is by a virus from thepicomaviridae family of viruses. In one embodiment, the viral infectionis by a picomaviridae virus selected from the group consisting of Humanrhinovirus 16 (HRV-16), Human enterovirus, Hepatitis A virus, Coxsackievirus (including type A24 variant CA24v), Echovirus, and Poliovirus.

In one embodiment, the viral infection is by a virus from theorthomyxoviridae family of viruses. In one embodiment, the viralinfection is by a orthomyxoviridae virus selected from the groupconsisting of Avian influenza (pathogenic strain (H5N1)), and Swineinfluenza including influenza C and the subtypes of influenza A known asH1N1, HIN2, H2N1, H3N1, H3N2, and H2N3.

In one embodiment, the viral infection is by a virus from theretroviridae family of viruses. In one embodiment, the viral infectionis by a retroviridae virus selected from the group consisting of humanimmunodeficiency virus (HIV-1).

In one embodiment, the viral infection is by a virus from thepapillomaviridae family of viruses. In one embodiment, the viralinfection is by a papillomaviridac virus selected from the groupconsisting of human papillomavirus (HPV).

In one embodiment, the viral infection is by a virus from theadenoviridae family of viruses. In one embodiment, the viral infectionis by a adenoviridac virus selected from the group consisting of humanadenovirus (Adenovirus serotype 14.)

In one embodiment, the viral infection is by a virus from the poxviridaefamily of viruses. In one embodiment, the viral infection is by apoxviridae virus selected from the group consisting of Humanorthopoxviruses, Monkeypox virus, Variola (VARV), including smallpox(Variola major virus) and Alastrim (Variola minor virus)), Cowpox (CPX),and Vaccinia (VACV or VV) viruses.

In one embodiment, the viral infection is by a virus from thepolyomaviridae family of viruses.

In one embodiment, the viral infection is by a virus causing viralhemorrhagic fever. In one embodiment, the virus causing viralhemorrhagic fever is selected from the group consisting of arenaviruses,filoviruses, bunyaviruses, and flaviviruses including Bundibugyo virus(BDBV), Sudan virus (SUDV), Tai Forest virus (TAFV) and Ebola virus(EBOV, formerly Zaire Ebola virus), Marburg, Lassa, Crimean-Congo, Seoulviruses, Lassa fever virus, Lujo virus and Argentine hemorrhagic fever.In one embodiment, the virus causing viral hemorrhagic fever is a SouthAmerican Haemorrhagic Fever virus selected from the group consisting ofChapare, Guanarito, Junin, Machupo, Sabia, Hantavirus hemorrhagic feverwith renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS).

In one embodiment, the viral infection is by a virus from theflaviviridae family of viruses. In one embodiment, the viral infectionis by a flaviviridae virus selected from the group consisting of Yellowfever, tick-borne encephalitis virus (TBEV), Kyasanur Forest diseasevirus, Omsk hemorrhagic fever virus, hepatitis B virus (HBV), hepatitisC virus (HCV), Dengue viruses (DEN-1, DEN-2, DEN-3 and DEN-4), West Nilevirus.

In one embodiment, the viral infection is by a virus from thetogaviridae family of viruses. In one embodiment, the viral infection isby a togaviridae virus selected from the group consisting of EasternEquine Encephalitis virus, Venezuelan equine encephalitis virus, Westernequine encephalitis virus, zoonotic alphaviruses (Chikungunya virus,Semliki Forest virus complex), and arbovirus.

In one embodiment, the viral infection is by a virus from thecoronaviridae family of viruses. In one embodiment, the viral infectionis by a coronaviridae virus selected from the group consisting of aSARS-associated coronavirus (SARS-CoV) and MERS (Middle East RespiratorySyndrome, MERS-CoV).

In one embodiment, the viral infection is by a virus from thebunyaviridae family of viruses. In one embodiment, the viral infectionis by a bunyaviridae virus selected from the group consisting of RiftValley fever.

The present disclosure contemplates the treatment of any viral infectionthat targets the fatty acid synthesis pathway in a host, and inparticular by modulating the activity of fatty acid synthase. Forexample, the present methods can be used to treat infections caused byAbelson leukemia virus, Abelson murine leukemia virus, Abelson's virus,Acute laryngotracheobronchitis virus, Adelaide River virus, Adenoassociated virus group, Adenovirus, African horse sickness virus,African swine fever virus, AIDS virus, Aleutian mink disease parvovirus,Alpharetrovirus, Alphavirus, ALV related virus, Amapari virus,Aphthovirus, Aquareovirus, Arbovirus, Arbovirus C, arbovirus group A,arbovirus group B, Arenavirus group, Argentine hemorrhagic fever virus,Argentine hemorrhagic fever virus, Arterivirus, Astrovirus, Atelineherpesvirus group, Aujezky's disease virus, Aura virus, Ausduk diseasevirus, Australian bat lyssavirus, Aviadenovirus, avian erythroblastosisvirus, avian infectious bronchitis virus, avian leukemia virus, avianleukosis virus, avian lymphomatosis virus, avian myeloblastosis virus,avian paramyxovirus, avian pneumoencephalitis virus, avianreticuloendotheliosis virus, avian sarcoma virus, avian type Cretrovirus group, Avihepadnavirus, Avipoxvirus, B virus, B19 virus,Babanki virus, baboon herpesvirus, baculovirus, Barmah Forest virus,Bebaru virus, Berrimah virus, Betaretrovirus, Birnavirus, Bittner virus,BK virus, Black Creek Canal virus, bluetongue virus, Bolivianhemorrhagic fever virus, Boma disease virus, border disease of sheepvirus, borna virus, bovine alphaherpesvirus 1, bovine alphaherpesvirus2, bovine coronavirus, bovine ephemeral fever virus, bovineimmunodeficiency virus, bovine leukemia virus, bovine leukosis virus,bovine mammillitis virus, bovine papillomavirus, bovine papularstomatitis virus, bovine parvovirus, bovine syncytial virus, bovine typeC oncovirus, bovine viral diarrhea virus, Buggy Creek virus, bulletshaped virus group, Bunyamwera virus supergroup, Bunyavirus, Burkitt'slymphoma virus, Bwamba Fever, CA virus, Calicivirus, Californiaencephalitis virus, camelpox virus, canarypox virus, canid herpesvirus,canine coronavirus, canine distemper virus, canine herpesvirus, canineminute virus, canine parvovirus, Cano Delgadito virus, caprine arthritisvirus, caprine encephalitis virus, Caprine Herpes Virus, Capripox virus,Cardiovirus, caviid herpesvirus 1, Cercopithecid herpesvirus 1,cercopithecine herpesvirus 1, Cercopithecine herpesvirus 2, Chandipuravirus, Changuinola virus, channel catfish virus, Charleville virus,chickenpox virus, Chikungunya virus, chimpanzee herpesvirus, chubreovirus, chum salmon virus, Cocal virus, Coho salmon reovirus, coitalexanthema virus, Colorado tick fever virus, Coltivirus, Columbia SKvirus, common cold virus, contagious ecthyma virus, contagious pustulardermatitis virus, Coronavirus, Corriparta virus, corvza virus, cowpoxvirus, coxsackie virus, CPV (cytoplasmic polyhedrosis virus), cricketparalysis virus, Crimean-Congo hemorrhagic fever virus, croup associatedvirus, Cryptovirus, Cypovirus, Cytomegalovirus, cytomegalovirus group,cytoplasmic polyhedrosis virus, deer papillomavirus, deltaretrovirus,dengue virus, Densovirus, Dependovirus, Dhori virus, diploma virus,Drosophila C virus, duck hepatitis B virus, duck hepatitis virus 1, duckhepatitis virus 2, duovirus, Duvenhage virus, Deformed wing virus DWV,eastern equine encephalitis virus, eastern equine encephalomyelitisvirus, EB virus, Ebola virus, Ebola-like virus, echo virus, echovirus,echovirus 10, echovirus 28, echovirus 9, ectromelia virus, EEE virus,EIA virus, EIA virus, encephalitis virus, encephalomyocarditis groupvirus, encephalomyocarditis virus, Enterovirus, enzyme elevating virus,enzyme elevating virus (LDH), epidemic hemorrhagic fever virus,epizootic hemorrhagic disease virus, Epstein-Barr virus, equidalphaherpesvirus 1, equid alphaherpesvirus 4, equid herpesvirus 2,equine abortion virus, equine arteritis virus, equine encephalosisvirus, equine infectious anemia virus, equine morbillivirus, equinerhinopneumonitis virus, equine rhinovirus, Eubenangu virus, European elkpapillomavirus, European swine fever virus, Everglades virus, Eyachvirus, felid herpesvirus 1, feline calicivirus, feline fibrosarcomavirus, feline herpesvirus, feline immunodeficiency virus, felineinfectious peritonitis virus, feline leukemia/sarcoma virus, felineleukemia virus, feline panleukopenia virus, feline parvovirus, felinesarcoma virus, feline syncytial virus, Filovirus, Flanders virus,Flavivirus, foot and mouth disease virus, Fort Morgan virus, FourCorners hantavirus, fowl adenovirus 1, fowlpox virus, Friend virus,Gammaretrovirus, GB hepatitis virus, GB virus, German measles virus,Getah virus, gibbon ape leukemia virus, glandular fever virus, goatpoxvirus, golden shinner virus, Gonometa virus, goose parvovirus,granulosis virus, Gross' virus, ground squirrel hepatitis B virus, groupA arbovirus, Guanarito virus, guinea pig cytomegalovirus, guinea pigtype C virus, Hantaan virus, Hantavirus, hard clam rcovirus, harefibroma virus, HCMV (human cytomegalovirus), hemadsorption virus 2,hemagglutinating virus of Japan, hemorrhagic fever virus, hendra virus,Henipaviruses, Hepadnavirus, hepatitis A virus, hepatitis B virus group,hepatitis C virus, hepatitis D virus, hepatitis delta virus, hepatitis Evirus, hepatitis F virus, hepatitis G virus, hepatitis nonA nonB virus,hepatitis virus, hepatitis virus (nonhuman), hepatoencephalomyelitisreovirus 3, Hepatovirus, heron hepatitis B virus, herpes B virus, herpessimplex virus, herpes simplex virus 1, herpes simplex virus 2,herpesvirus, herpesvirus 7, Herpesvirus ateles, Herpesvirus hominis,Herpesvirus infection, Herpesvirus saimiri, Herpesvirus suis,Herpesvirus varicellae, Highlands J virus, Hirame rhabdovirus, hogcholera virus, human adenovirus 2, human alphaherpesvirus 1, humanalphaherpesvirus 2, human alphaherpesvirus 3, human B lymphotropicvirus, human betaherpesvirus 5, human coronavirus, human cytomegalovirusgroup, human foamy virus, human gammaherpesvirus 4, humangammaherpesvirus 6, human hepatitis A virus, human herpesvirus 1 group,human herpesvirus 2 group, human herpesvirus 3 group, human herpesvirus4 group, human herpesvirus 6, human herpesvirus 8, humanimmunodcficiency virus, human immunodeficiency virus 1, humanimmunodeficiency virus 2, human papillomavirus, human T cell leukemiavirus, human T cell leukemia virus I, human T cell leukemia virus II,human T cell leukemia virus III, human T cell lymphoma virus I, human Tcell lymphoma virus II, human T cell lymphotropic virus type 1, human Tcell lymphotropic virus type 2, human T lymphotropic virus I, human Tlymphotropic virus II, human T lymphotropic virus III, Ichnovirus,infantile gastroenteritis virus, infectious bovine rhinotracheitisvirus, infectious haematopoietic necrosis virus, infectious pancreaticnecrosis virus, influenza virus A, influenza virus B, influenza virus C,influenza virus D, influenza virus pr8, insect iridescent virus, insectvirus, iridovirus, Japanese B virus, Japanese encephalitis virus, JCvirus, Junin virus, Kaposi's sarcoma-associated herpesvirus, Kemerovovirus, Kilham's rat virus, Klamath virus, Kolongo virus, Koreanhemorrhagic fever virus, kumba virus, Kysanur forest disease virus,Kyzylagach virus, La Crosse virus, lactic dehydrogenase elevating virus,lactic dehydrogenase virus, Lagos bat virus, Langur virus, lapineparvovirus, Lassa fever virus, Lassa virus, latent rat virus, LCM virus,Leaky virus, Lentivirus, Leporipoxvirus, leukemia virus, leukovirus,lumpy skin disease virus, lymphadenopathy associated virus,Lymphocryptovirus, lymphocytic choriomeningitis virus,lymphoproliferative virus group, Machupo virus, mad itch virus,mammalian type B oncovirus group, mammalian type B retroviruses,mammalian type C retrovirus group, mammalian type D retroviruses,mammary tumor virus, Mapuera virus, Marburg virus, Marburg-like virus,Mason Pfizer monkey virus, Mastadenovirus, Mayaro virus, ME virus,measles virus, Menangle virus, Mengo virus, Mengovirus, Middelburgvirus, milkers nodule virus, mink enteritis virus, minute virus of mice,MLV related virus, MM virus, Mokola virus, Molluscipoxvirus, Molluscumcontagiosum virus, monkey B virus, monkeypox virus, Mononegavirales,Morbillivirus, Mount Elgon bat virus, mouse cytomegalovirus, mouseencephalomyelitis virus, mouse hepatitis virus, mouse K virus, mouseleukemia virus, mouse mammary tumor virus, mouse minute virus, mousepneumonia virus, mouse poliomyelitis virus, mouse polyomavirus, mousesarcoma virus, mousepox virus, Mozambique virus, Mucambo virus, mucosaldisease virus, mumps virus, murid betaherpesvirus 1, muridcytomegalovirus 2, murine cytomegalovirus group, murineencephalomyelitis virus, murine hepatitis virus, murine leukemia virus,murine nodule inducing virus, murine polyomavirus, murine sarcoma virus,Muromegalovirus, Murray Valley encephalitis virus, myxoma virus,Myxovirus, Myxovirus multiforme, Myxovirus parotitidis, Nairobi sheepdisease virus, Nairovirus, Nanimavirus, Nariva virus, Ndumo virus,Neethling virus, Nelson Bay virus, neurotropic virus, New WorldArenavirus, newbom pneumonitis virus, Newcastle disease virus, Nipahvirus, noncytopathogenic virus, Norwalk virus, nuclear polyhedrosisvirus (NPV), nipple neck virus, O'nyong'nyong virus, Ockelbo virus,oncogenic virus, oncogenic viruslike particle, oncomavirus, Orbivirus,Orf virus, Oropouche virus, Orthohepadnavirus, Orthomvxovirus,Orthopoxvirus, Orthoreovirus, Orungo, ovine papillomavirus, ovinecatarrhal fever virus, owl monkey herpesvirus, Palyam virus,Papillomavirus, Papillomavirus sylvilagi, Papovavirus, parainfluenzavirus, parainfluenza virus type 1, parainfluenza virus type 2,parainfluenza virus type 3, parainfluenza virus type 4, Paramyxovirus,Parapoxvirus, paravaccinia virus, Parvovirus, Parvovirus B19, parvovirusgroup, Pestivirus, Phlebovirus, phocine distemper virus, Picodnavirus,Picomavirus, pig cytomegalovirus-pigeonpox virus, Piry virus, Pixunavirus, pneumonia virus of mice, Pneumovirus, poliomyelitis virus,poliovirus, Polydnavirus, polyhedral virus, polyoma virus, Polyomavirus,Polyomavirus bovis, Polyomavirus cercopitheci, Polyomavirus hominis 2,Polyomavirus maccacae 1, Polyomavirus muris 1, Polyomavirus muris 2,Polyomavirus papionis 1, Polyomavirus papionis 2, Polyomavirussylvilagi, Pongine herpesvirus 1, porcine epidemic diarrhea virus,porcine hemagglutinating encephalomyelitis virus, porcine parvovirus,porcine transmissible gastroenteritis virus, porcine type C virus, poxvirus, poxvirus, poxvirus variolac, Prospect Hill virus, Provirus,pseudocowpox virus, pseudorabies virus, psittacinepox virus, quailpoxvirus, rabbit fibroma virus, rabbit kidney vaculolating virus, rabbitpapillomavirus, rabies virus, raccoon parvovirus, raccoonpox virus,Ranikhet virus, rat cytomegalovirus, rat parvovirus, rat virus,Rauscher's virus, recombinant vaccinia virus, recombinant virus,reovirus, reovirus 1, reovirus 2, reovirus 3, reptilian type C virus,respiratory infection virus, respiratory syncytial virus, respiratoryvirus, reticuloendotheliosis virus, Rhabdovirus, Rhabdovirus carpia,Rhadinovirus, Rhinovirus, Rhizidiovirus, Rift Valley fever virus,Riley's virus, rinderpest virus, RNA tumor virus, Ross River virus,Rotavirus, rougeole virus, Rous sarcoma virus, rubella virus, rubeolavirus, Rubivirus, Russian autumn encephalitis virus, SA 11 simian virus,SA2 virus, Sabia virus, Sagiyama virus, Saimirine herpesvirus 1,salivary gland virus, sandfly fever virus group, Sandjimba virus, SARSvirus, SDAV (sialodacryoadenitis virus), sealpox virus, Semliki ForestVirus, Seoul virus, sheeppox virus, Shope fibroma virus, Shope papillomavirus, simian foamy virus, simian hepatitis A virus, simian humanimmunodeficiency virus, simian immunodeficiency virus, simianparainfluenza virus, simian T cell lymphotrophic virus, simian virus,simian virus 40, Simplexvirus, Sin Nombre virus, Sindbis virus, smallpoxvirus, South American hemorrhagic fever viruses, sparrowpox virus,Spumavirus, squirrel fibroma virus, squirrel monkey retrovirus, SSV 1virus group, STLV (simian T lymphotropic virus) type I, STLV (simian Tlymphotropic virus) type II, STLV (simian T lymphotropic virus) typeIII, stomatitis papulosa virus, submaxillary virus, suidalphaherpesvirus 1, suid herpesvirus 2, Suipoxvirus, swamp fever virus,swinepox virus, Swiss mouse leukemia virus, TAC virus, Tacaribe complexvirus, Tacaribe virus, Tanapox virus, Taterapox virus, Tench reovirus,Theiler's encephalomyelitis virus, Theiler's virus, Thogoto virus,Thottapalayam virus, Tick bome encephalitis virus, Tioman virus,Togavirus, Torovirus, tumor virus, Tupaia virus, turkey thinotracheitisvirus, turkeypox virus, type C retroviruses, type D oncovirus, type Dretrovirus group, ulcerative disease rhabdovirus, Una virus, Uukuniemivirus group, vaccinia virus, vacuolating virus, varicella zoster virus,Varicellovirus, Varicola virus, variola major virus, variola virus,Vasin Gishu disease virus, VEE virus, Venezuelan equine encephalitisvirus, Venezuelan equine encephalomyelitis virus, Venezuelan hemorrhagicfever virus, vesicular stomatitis virus, Vesiculovirus, Vilyuisk virus,viper retrovirus, viral haemorrhagic septicemia virus, Visna Macdivirus, Visna virus, volepox virus, VSV (vesicular stomatitis virus),Wallal virus, Warrego virus, wart virus, WEE virus, West Nile virus,western equine encephalitis virus, western equine encephalomyelitisvirus, Whataroa virus, Winter Vomiting Virus, woodchuck hepatitis Bvirus, woolly monkey sarcoma virus, wound tumor virus, WRSV virus, Yabamonkey tumor virus, Yaba virus, Yatapoxvirus, yellow fever virus, andthe Yug Bogdanovac virus.

Utility in Metabolic Disorders

In various aspects, the compounds of the present disclosure have utilityin the treating of metabolic diseases. FASN has been demonstrated to beinvolved in regulation of glucose, lipids and cholesterol metabolism.Mice with a liver-specific inactivation of FASN have normal physiologyunless fed a zero-fat diet, in which case they develop hypoglycemia andfatty liver, both of which are reversed with dietary fat. (Chakravarthy,M. V., et al. (2005) Cell Metabolism 1:309-322). Db/+mice fed a highfructose diet exhibit reduced liver triglyceride levels and improvedinsulin sensitivity when treated for 28 days with platensimycin, acovealent inhibitor of FASN. (Wu, M. et al. (2011) PNAS108(13):5378-5383). Ambient glucose levels are also reduced in db/dbmice following treatment with platensimycin. These results provideevidence that inhibiting FASN can yield therapeutically relevantbenefits in animal models of diabetes and related metabolic disorders.Thus the disclosed FASN inhibitors are useful in the treatment ofdisorders characterized by disregulation in these systems. Withoutlimitation, examples include steatosis and diabetes.

Anticancer Activity

In various aspects, the present disclosure provides methods for treatingcancer in a subject, the method comprising administering to a subject inneed of such treatment an effective amount of a compound of Formulae(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or asprovided in Table 1. In further aspects, compounds having Formula (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) or asprovided in Table 1 can be used for the manufacture of a medicament fortreating cancer.

In certain aspects, the present disclosure provides a method forinhibiting tumor cell growth in a subject, the method comprisingadministering to a subject in need of such treatment an effective amountof a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI) or as provided in Table 1. In further aspects,the tumor can be derived from ovary, breast, lung, thyroid, lymph node,kidney, ureter, bladder, ovary, teste, prostate, bone, skeletal muscle,bone marrow, stomach, esophagus, small bowel, colon, rectum, pancreas,liver, smooth muscle, brain, spinal cord, nerves, ear, eye, nasopharynx,oropharynx, salivary gland, or heart tissue. In certain aspects, thepresent compounds can be administered concurrently with one or moreadditional anti-cancer treatments.

In another embodiment, the tumor is a cancer selected from the groupconsisting of breast cancer; non-small-cell lung cancer; antle celllymphoma; renal cell carcinoma; acute myelogenous leukemia (AML);chronic myelogenous leukemia (CML); diffuse large B cell lymphoma(DLBCL); sarcoma; rhabdomyosarcoma; ovarian cancer; endometrial tumors;non small cell lung carcinoma (NSCLC); small cell, squamous, large celland adenocarcinoma; lung cancer; colon cancer; colorectal tumors;KRAS-mutated colorectal tumors; gastric carcinomas; hepatocellulartumors; liver tumors; primary melanomas; pancreatic tumors; pancreaticcancer; prostate carcinoma; thyroid carcinoma; follicular thyroidcarcinoma; anaplastic large cell lymphoma (ALCL); hamaratomas,angiomyelolipomas, TSC-associated and sporadic lymphangioleiomyomatosis:Cowden's disease (multiple hamaratoma syndrome); sclerosing hemangioma;Peutz-Jeghers syndrome (PJS); head and neck cancer; neurofibromatosis;macular degeneration; macular edema; myeloid leukemia; systemic lupus;and autoimmune lymphoproliferative syndrome (ALPS).

In a further embodiment, the tumor is a cancer selected from the groupconsisting of breast cancer; antle cell lymphoma; renal cell carcinoma;acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML);diffuse large B cell lymphoma (DLBCL); sarcoma; rhabdomyosarcoma;ovarian cancer; endometrial tumors; non small cell lung carcinoma(NSCLC); small cell, squamous, large cell and adenocarcinoma; lungcancer; colon cancer; colorectal tumors; KRAS-mutated colorectal tumors;gastric carcinomas; hepatocellular tumors; liver tumors; primarymelanomas; pancreatic tumor; pancreatic cancer; prostate carcinoma;thyroid carcinoma; follicular thyroid carcinoma; anaplastic large celllymphoma (ALCL); hamaratomas, angiomyelolipomas. TSC-associated andsporadic lymphangioleiomyomatosis: Cowden's disease (multiple hamaratomasyndrome); sclerosing hemangioma; Peutz-Jeghers syndrome (PJS); head andneck cancer; neurofibromatosis: macular degeneration; macular edema;myeloid leukemia; systemic lupus; and autoimmune lymphoproliferativesyndrome (ALPS).

In certain aspects, the present disclosure provides a method fortreating pancreatic cancer in a subject, the method comprisingadministering to a subject in need of such treatment an effective amountof a compound of Formulae (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI) or as provided in Table 1.

In certain aspects, the present disclosure provides for a method oftreating colon cancer in a subject, the method comprising administeringto a subject in need of such treatment an effective amount of a compoundof Formulae (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),(XI) or as provided in Table 1.

Rapidly proliferating cancer cells activate the fatty acid synthesispathway to supply the high levels of lipids needed for membrane assemblyand oxidative metabolism. (Flavin, R. et al. (2010) Future Oncology.6(4):551-562) Inhibitors of fatty acid synthesis have demonstrated invivo activity in preclinical cancer models. (Orita, H. et al. (2007)Clinical Cancer Research. 13(23):7139-7145 and Puig, T. et al. (2011)Breast Cancer Research. 13(6):R₁₃₁) Additionally, fatty acid synthesissupports new blood vessel formation and inhibitors of this pathway haveactivity in in vitro models of angiogenesis. (Browne, C. D., et al.(2006) The FASEB Journal, 20(12):2027-2035). The presently disclosedcompounds demonstrated the ability to selectively induce cell-cyclearrest in HUVEC cells without causing general cell death by apoptosis.See EXAMPLES.

The cancer treatment of the present invention includes an anti-tumoreffect that may be assessed by conventional means such as the responserate, the time to disease progression and/or the survival rate.Anti-tumor effects of the present invention include, but are not limitedto, inhibition of tumor growth, tumor growth delay, regression of tumor,shrinkage of tumor, increased time to regrowth of tumor on cessation oftreatment and slowing of disease progression. For example, it isexpected that when the combination of the present invention isadministered to a warm-blooded animal such as a human, in need oftreatment for cancer involving a solid tumor, such a method of treatmentwill produce an effect, as measured by, for example, one or more of: theextent of the anti-tumor effect, the response rate, the time to diseaseprogression and the survival rate.

Methods of Treatment

Also provided herein are pharmaceutical compositions comprising thecompounds of the present disclosure. The present compositions andmethods have antiviral and/or anticancer activity.

In various aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Formulae (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or (XI) and apharmaceutically acceptable carrier, excipient, or diluent.

In certain aspects, the present disclosure provides pharmaceuticalcompositions comprising any one of the compounds of Table 1 and apharmaceutically acceptable carrier, excipient, or diluent.

Certain aspects of the present disclosure relates to methods of usingpharmaceutical compositions and kits comprising one or more agents thatinhibit the fatty acid synthesis pathway to inhibit or decrease a viralinfection or for the treatment of cancer. Certain aspects of the presentdisclosure relates to methods of using pharmaceutical compositions andkits comprising one or more agents that inhibit fatty acid synthase toinhibit or decrease a viral infection or for the treatment of cancer.Another aspect of the present invention provides methods, pharmaceuticalcompositions, and kits for the treatment of animal subjects having aviral infection or cancer or at risk of developing a viral infection orcancer. The term “subject” as used herein includes humans as well asother mammals. The term “treating” as used herein includes achieving atherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying viralinfection. Also, a therapeutic benefit is achieved with the eradicationor amelioration of one or more of the physiological symptoms associatedwith the underlying viral infection such that an improvement is observedin the animal subject, notwithstanding the fact that the subject canstill be afflicted with the underlying virus.

For aspects where a prophylactic benefit is desired, a pharmaceuticalcomposition of the invention can be administered to a patient at risk ofdeveloping viral infection such as HRV, or HIV, or to a patientreporting one or more of the physiological symptoms of a viralinfection, even though a diagnosis of the condition may not have beenmade. Administration can prevent the viral infection from developing, orit can reduce, lessen, shorten and/or otherwise ameliorate the viralinfection that develops. The pharmaceutical composition can modulate thefatty acid synthesis pathway, i.e., FAS gene expression or FASN proteinactivity. Wherein, the term modulate includes inhibition of the fattyacid synthesis pathway, i.e., FASN gene expression or FASN proteinactivity or alternatively activation of the fatty acid synthesispathway, i.e., FASN gene expression or FASN protein activity.

Reducing the activity of the fatty acid synthesis pathway, i.e., FASNgene expression or FASN protein activity, is also referred to as“inhibiting” the fatty acid synthesis pathway, i.e., FASN geneexpression or FASN protein activity. The term “inhibits” and itsgrammatical conjugations, such as “inhibitory,” do not require completeinhibition, but refer to a reduction in fatty acid synthesis activity,i.e., FASN gene expression or FASN protein activity. In another aspect,such reduction is by at least 50%, at least 75%, at least 90%, and canbe by at least 95% of the activity of the enzyme in the absence of theinhibitory effect, i.e., in the absence of an inhibitor. Conversely, thephrase “does not inhibit” and its grammatical conjugations refer tosituations where there is less than 20%, less than 10%, and can be lessthan 5%, of reduction in enzyme activity in the presence of the agent.Further the phrase “does not substantially inhibit” and its grammaticalconjugations refer to situations where there is less than 30%, less than20%, and in some aspects less than 10% of reduction in enzyme activityin the presence of the agent.

Increasing the activity of the fatty acid synthesis pathway, i.e., FASNgene expression or FASN protein activity, is also referred to as“activating” the fatty acid synthesis pathway, i.e., FASN geneexpression or FASN protein activity. The term “activated” and itsgrammatical conjugations, such as “activating,” do not require completeactivation, but refer to an increase in fatty acid synthesis pathwayactivity, i.e., FASN gene expression or FASN protein activity. Inanother aspect such increase is by at least 50%, at least 75%, at least90%, and can be by at least 95% of the activity of the enzyme in theabsence of the activation effect, i.e., in the absence of an activator.Conversely, the phrase “does not activate” and its grammaticalconjugations refer to situations where there is less than 20%, less than10%, and can be less than 5%, of an increase in enzyme activity in thepresence of the agent. Further the phrase “does not substantiallyactivate” and its grammatical conjugations refer to situations wherethere is less than 30%, less than 20%, and in another aspect less than10% of an increase in enzyme activity in the presence of the agent.

The ability to reduce enzyme activity is a measure of the potency or theactivity of an agent, or combination of agents, towards or against theenzyme. Potency can be measured by cell free, whole cell and/or in vivoassays in terms of IC50, K_(i) and/or ED50 values. An IC50 valuerepresents the concentration of an agent required to inhibit enzymeactivity by half (50%) under a given set of conditions. A K_(i) valuerepresents the equilibrium affinity constant for the binding of aninhibiting agent to the enzyme. An ED50 value represents the dose of anagent required to effect a half-maximal response in a biological assay.Further details of these measures will be appreciated by those ofordinary skill in the art, and can be found in standard texts onbiochemistry, enzymology, and the like.

The present invention also includes kits that can be used to treat viralinfections or treat cancer. These kits comprise an agent or combinationof agents that inhibit the fatty acid synthesis pathway, i.e., FASN geneexpression or FASN protein activity, and optionally instructionsteaching the use of the kit according to the various methods andapproaches described herein. Such kits can also include information,such as scientific literature references, package insert materials,clinical trial results, and/or summaries of these and the like, whichindicate or establish the activities and/or advantages of the agent.Such information can be based on the results of various studies, forexample, studies using experimental animals involving in vive models andstudies based on human clinical trials. Kits described herein can beprovided, marketed and/or promoted to health providers, includingphysicians, nurses, pharmacists, formulary officials, and the like.

Formulations, Routes of Administration, and Effective Doses

Yet another aspect of the present invention relates to formulations,routes of administration and effective doses for pharmaceuticalcompositions comprising an agent or combination of agents of the instantinvention. Such pharmaceutical compositions can be used to treat viralinfections as described above.

Compounds of the invention can be administered as pharmaceuticalformulations including those suitable for oral (including buccal andsub-lingual), rectal, nasal, topical, transdermal patch, pulmonary,vaginal, suppository, or parenteral (including intramuscular,intraarterial, intrathecal, intradermal, intraperitoneal, subcutaneousand intravenous) administration or in a form suitable for administrationby aerosolization, inhalation or insufflation. General information ondrug delivery systems can be found in Ansel et al., PharmaceuticalDosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins,Baltimore Md. (1999).

In various aspects, the pharmaceutical composition includes carriers andexcipients (including but not limited to buffers, carbohydrates,mannitol, proteins, polypeptides or amino acids such as glycine,antioxidants, bacteriostats, chelating agents, suspending agents,thickening agents and/or preservatives), water, oils including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like, saline solutions,aqueous dextrose and glycerol solutions, flavoring agents, coloringagents, detackifiers and other acceptable additives, adjuvants, orbinders, other pharmaceutically acceptable auxiliary substances asrequired to approximate physiological conditions, such as pH bufferingagents, tonicity adjusting agents, emulsifying agents, wetting agentsand the like. Examples of excipients include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. In another aspect, thepharmaceutical preparation is substantially free of preservatives. Inanother aspect, the pharmaceutical preparation can contain at least onepreservative. General methodology on pharmaceutical dosage forms isfound in Ansel et al., Pharmaceutical Dosage Forms and Drug DeliverySystems (Lippencott Williams & Wilkins, Baltimore Md. (1999)). It willbe recognized that, while any suitable carrier known to those ofordinary skill in the art can be employed to administer the compositionsof this invention, the type of carrier will vary depending on the modeof administration.

Compounds can also be encapsulated within liposomes using well-knowntechnology. Biodegradable microspheres can also be employed as carriersfor the pharmaceutical compositions of this invention. Suitablebiodegradable microspheres are disclosed, for example, in U.S. Pat. Nos.4,897,268; 5,075,109; 5,928,647; 5,811,128; 5,820,883; 5,853,763,5,814,344 and 5,942,252.

The compound can be administered in liposomes or microspheres (ormicroparticles). Methods for preparing liposomes and microspheres foradministration to a patient are well known to those of skill in the art.U.S. Pat. No. 4,789,734, the contents of which are hereby incorporatedby reference, describes methods for encapsulating biological materialsin liposomes. Essentially, the material is dissolved in an aqueoussolution, the appropriate phospholipids and lipids added, along withsurfactants if required, and the material dialyzed or sonicated, asnecessary. A review of known methods is provided by G. Gregoriadis,Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, pp.2.sup.87-341 (Academic Press, 1979).

Microspheres formed of polymers or proteins are well known to thoseskilled in the art, and can be tailored for passage through thegastrointestinal tract directly into the blood stream. Alternatively,the compound can be incorporated and the microspheres, or composite ofmicrospheres, implanted for slow release over a period of time rangingfrom days to months. See, for example, U.S. Pat. Nos. 4,906,474,4,925,673 and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contentsof which are hereby incorporated by reference.

The concentration of drug can be adjusted, the pH of the solutionbuffered and the isotonicity adjusted to be compatible with intravenousinjection, as is well known in the art.

The compounds of the invention can be formulated as a sterile solutionor suspension, in suitable vehicles, well known in the art. Thepharmaceutical compositions can be sterilized by conventional,well-known sterilization techniques, or can be sterile filtered. Theresulting aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterilesolution prior to administration. Suitable formulations and additionalcarriers are described in Remington “The Science and Practice ofPharmacy” (20^(th) Ed., Lippincott Williams & Wilkins, Baltimore Md.),the teachings of which are incorporated by reference in their entiretyherein.

The agents or their pharmaceutically acceptable salts can be providedalone or in combination with one or more other agents or with one ormore other forms. For example a formulation can comprise one or moreagents in particular proportions, depending on the relative potencies ofeach agent and the intended indication. For example, in compositions fortargeting two different host targets, and where potencies are similar,about a 1:1 ratio of agents can be used. The two forms can be formulatedtogether, in the same dosage unit i.e., in one cream, suppository,tablet, capsule, aerosol spray, or packet of powder to be dissolved in abeverage, or each form can be formulated in a separate unit, i.e., twocreams, two suppositories, two tablets, two capsules, a tablet and aliquid for dissolving the tablet, two aerosol sprays, or a packet ofpowder and a liquid for dissolving the powder, etc.

The term “pharmaceutically acceptable salt” means those salts whichretain the biological effectiveness and properties of the agents used inthe present invention, and which are not biologically or otherwiseundesirable. For example, a pharmaceutically acceptable salt does notinterfere with the beneficial effect of an agent of the invention ininhibiting the fatty acid synthesis pathway, i.e., inhibiting FASN geneexpression or FASN protein activity.

Typical salts are those of the inorganic ions, such as, for example,sodium, potassium, calcium, magnesium ions, and the like. Such saltsinclude salts with inorganic or organic acids, such as hydrochloricacid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid,methanesulfonic acid, p-toluenesulfonic acid, acetic acid, fumaric acid,succinic acid, lactic acid, mandelic acid, malic acid, citric acid,tartaric acid or maleic acid. In addition, if the agent(s) contain acarboxy group or other acidic group, it can be converted into apharmaceutically acceptable addition salt with inorganic or organicbases. Examples of suitable bases include sodium hydroxide, potassiumhydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine,diethanolamine, triethanolamine, and the like.

A pharmaceutically acceptable ester or amide refers to those whichretain biological effectiveness and properties of the agents used in thepresent invention, and which are not biologically or otherwiseundesirable. For example, the ester or amide does not interfere with thebeneficial effect of an agent of the invention in inhibiting the fattyacid synthesis pathway, i.e., inhibiting FASN gene expression or FASNprotein activity. Typical esters include ethyl, methyl, isobutyl,ethylene glycol, and the like. Typical amides include unsubstitutedamides, alkyl amides, dialkyl amides, and the like.

In another aspect, an agent can be administered in combination with oneor more other compounds, forms, and/or agents, i.e., as described above.Pharmaceutical compositions comprising combinations of a fatty acidsynthesis pathway inhibitor i.e., an inhibitor or FASN gene expressionor FASN protein activity with one or more other active agents can beformulated to comprise certain molar ratios. For example, molar ratiosof about 99:1 to about 1:99 of a fatty acid synthesis pathway inhibitori.e., an inhibitor of FASN gene expression or FASN protein activity, tothe other active agent can be used. In some subset of the aspects, therange of molar ratios of fatty acid synthesis pathway inhibitor i.e., aninhibitor of FASN gene expression or FASN protein activity: other activeagent is selected from about 80:20 to about 20:80; about 75:25 to about25:75, about 70:30 to about 30:70, about 66:33 to about 33:66, about60:40 to about 40:60; about 50:50; and about 90:10 to about 10:90. Themolar ratio of a fatty acid synthesis pathway inhibitor i.e., aninhibitor of FASN gene expression or FASN protein activity: other activeagent can be about 1:9, and in another aspect can be about 1:1. The twoagents, forms and/or compounds can be formulated together, in the samedosage unit i.e., in one cream, suppository, tablet, capsule, or packetof powder to be dissolved in a beverage; or each agent, form, and/orcompound can be formulated in separate units, i.e., two creams,suppositories, tablets, two capsules, a tablet and a liquid fordissolving the tablet, an aerosol spray a packet of powder and a liquidfor dissolving the powder, etc.

If necessary or desirable, the agents and/or combinations of agents canbe administered with still other agents. The choice of agents that canbe co-administered with the agents and/or combinations of agents of theinstant invention can depend, at least in part, on the condition beingtreated. Agents of particular use in the formulations of the presentinvention include, for example, any agent having a therapeutic effectfor a viral infection, including, i.e., drugs used to treat inflammatoryconditions. For example, in treatments for HRV, in some aspectsformulations of the instant invention can additionally contain one ormore conventional anti-inflammatory drugs, such as an NSAID. i.e.,ibuprofen, naproxen, acetaminophen, ketoprofen, or aspirin. In somealternative aspects for the treatment of influenza formulations of theinstant invention can additionally contain one or more conventionalinfluenza antiviral agents, such as amantadine, rimantadine, zanamivir,and oseltamivir. In treatments for retroviral infections, such as HIV,formulations of the instant invention can additionally contain one ormore conventional antiviral drug, such as protease inhibitors(lopinavir/ritonavir (Kaletra), indinavir (Crixivan), ritonavir(Norvir), nelfinavir (Viracept), saquinavir hard gel capsules(Invirase), atazanavir (Reyataz), amprenavir (Agenerase), fosamprenavir(Telzir), tipranavir (Aptivus)), reverse transcriptase inhibitors,including non-Nucleoside and Nucleoside/nucleotide inhibitors (AZT(zidovudine, Retrovir), ddI (didanosine, Videx), 3TC (lamivudine,Epivir), d4T (stavudine, Zerit), abacavir (Ziagen), FTC (emtricitabine,Emtriva), tenofovir (Viread), efavirenz (Sustiva) and nevirapine(Viramune)), fusion inhibitors T20 (enfuvirtide. Fuzeon), integraseinhibitors (MK-0518 and GS-9137), and maturation inhibitors (PA-457(Bevirimat)). As another example, formulations can additionally containone or more supplements, such as vitamin C, E or other anti-oxidants.

In certain aspects, the compounds of the present disclosure can beadministered in combination with a known cancer therapeutic. Forexample, the compounds can be administered in combination withpaclitaxel (commercially available as Taxol, Bristol-Myers Squibb),doxorubicin (also known under the trade name Adriamycin), vincristine(known under the trade names Oncovin, Vincasar PES, and Vincrex),actinomycin D, altretamine, asparaginase, bleomycin, busulphan,cabazitaxel, capecitabine, carboplatin, carmustine, chlorambucil,cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin,docetaxel, epirubicin, etoposide, fludarabine, fluorouracil,gemcitabine, hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine,melphalan, mercaptopurine, methotrexate, mitomycin, mitozantrone,oxaliplatin, procarbazine, steroids, streptozocin, taxotere,tamozolomide, thioguanine, thiotepa, tomudex, topotecan, treosulfan, UFT(uracil-tegufur), vinblastine, vindesine, agents targeting immunemodualtors such as PD-1, PDL-1, and IDOl, i.e. nivolumab, pembrolizumab,MPDL3280A, and MEDI4736; agents targeting DNA repair deficiency, i.e.olaparib; agents targeting receptor tyrosine kinases such as EGFR,ERBB2, c-MET, VEGFR2, and IGFR1, i.e. erlotinib, necitumumab,traztuzamab, pertuzamab, lapatinib, crizotinib, cabozantinib,onartuamab, ramucirumab, or bevacizumab; agents targeting the MAPK/ERK,MAPK kinase, MEK1 and/or MEK2, i.e., selumetinib or trametinib; agentstargeting hormone receptors such as the androgen and estrogen receptors,i.e. enzalutamide, abiraterone, or tamoxifen; agents targeting the MAPkinase or PI3K-AKT pathways, i.e. cobimetinib, vemurafenib, andeverolimus; Hcr2 (ErbB2) pathway blockers such as lapatinib,trastuzumab, and Kadyzla; mTOR blockers such as ralapogs (i.e.,sirolimus); mTORC1/mTORC1 inhibitors; Angiogenesis or VEGFR pathwayblockers such as avastin, nexavar or sutent; Aromatase modulators suchas exemtesane or femora; Androgen signaling modulators such asenzalutamide, bicalutamide; and B-RAF blockers such as Tafinlar orZelboraf, or the like.

The agent(s) (or pharmaceutically acceptable salts, esters or amidesthereof) can be administered per se or in the form of a pharmaceuticalcomposition wherein the active agent(s) is in an admixture or mixturewith one or more pharmaceutically acceptable carriers. A pharmaceuticalcomposition, as used herein, can be any composition prepared foradministration to a subject. Pharmaceutical compositions for use inaccordance with the present invention can be formulated in conventionalmanner using one or more physiologically acceptable carriers, comprisingexcipients, diluents, and/or auxiliaries, i.e., which facilitateprocessing of the active agents into preparations that can beadministered. Proper formulation can depend at least in part upon theroute of administration chosen. The agent(s) useful in the presentinvention, or pharmaceutically acceptable salts, esters, or amidesthereof, can be delivered to a patient using a number of routes or modesof administration, including oral, buccal, topical, rectal, transdermal,transmucosal, subcutaneous, intravenous, and intramuscular applications,as well as by inhalation.

For oral administration, the agents can be formulated readily bycombining the active agent(s) with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the agents of the inventionto be formulated as tablets, including chewable tablets, pills, dragees,capsules, lozenges, hard candy, liquids, gels, syrups, slurries,powders, suspensions, elixirs, wafers, and the like, for oral ingestionby a patient to be treated. Such formulations can comprisepharmaceutically acceptable carriers including solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents. Asolid carrier can be one or more substances which can also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material. In powders, the carrier generally is a finelydivided solid which is a mixture with the finely divided activecomponent. In tablets, the active component generally is mixed with thecarrier having the necessary binding capacity in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from about one (1) to about seventy (70) percent ofthe active compound. Suitable carriers include but are not limited tomagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Generally, the agents of the invention will be included at concentrationlevels ranging from about 0.5%, about 5%, about 10%, about 20%, or about30% to about 50%, about 60%, about 70%, about 80% or about 90% by weightof the total composition of oral dosage forms, in an amount sufficientto provide a desired unit of dosage.

Aqueous suspensions for oral use can contain agent(s) of this inventionwith pharmaceutically acceptable excipients, such as a suspending agent(i.e., methyl cellulose), a wetting agent (i.e., lecithin, lysolecithinand/or a long-chain fatty alcohol), as well as coloring agents,preservatives, flavoring agents, and the like.

In another aspect, oils or non-aqueous solvents can be required to bringthe agents into solution, due to, for example, the presence of largelipophilic moieties. Alternatively, emulsions, suspensions, or otherpreparations, for example, liposomal preparations, can be used. Withrespect to liposomal preparations, any known methods for preparingliposomes for treatment of a condition can be used. See, for example,Bangham, et al., J. Mol. Biol. 23: 238-252 (1965) and Szoka, et al.,Proc. Natl Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein byreference. Ligands can also be attached to the liposomes to direct thesecompositions to particular sites of action. Agents of this invention canalso be integrated into foodstuffs, i.e., cream cheese, butter, saladdressing, or ice cream to facilitate solubilization, administration,and/or compliance in certain patient populations.

Pharmaceutical preparations for oral use can be obtained as a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; flavoring elements, cellulose preparations such as, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone (PVP). If desired, disintegrating agents can beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate. The agents can also beformulated as a sustained release preparation.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active agents.

Pharmaceutical preparations that can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active agents can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for administration.

Other forms suitable for oral administration include liquid formpreparations including emulsions, syrups, elixirs, aqueous solutions,aqueous suspensions, or solid form preparations which are intended to beconverted shortly before use to liquid form preparations. Emulsions canbe prepared in solutions, for example, in aqueous propylene glycolsolutions or can contain emulsifying agents, for example, such aslecithin, sorbitan monooleate, or acacia. Aqueous solutions can beprepared by dissolving the active component in water and adding suitablecolorants, flavors, stabilizers, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents. Suitable fillers or carriers with whichthe compositions can be administered include agar, alcohol, fats,lactose, starch, cellulose derivatives, polysaccharides,polyvinylpyrrolidone, silica, sterile saline and the like, or mixturesthereof used in suitable amounts. Solid form preparations includesolutions, suspensions, and emulsions, and can contain, in addition tothe active component, colorants, flavors, stabilizers, buffers,artificial and natural sweeteners, dispersants, thickeners, solubilizingagents, and the like.

A syrup or suspension can be made by adding the active compound to aconcentrated, aqueous solution of a sugar, i.e., sucrose, to which canalso be added any accessory ingredients. Such accessory ingredients caninclude flavoring, an agent to retard crystallization of the sugar or anagent to increase the solubility of any other ingredient, i.e., as apolyhydric alcohol, for example, glycerol or sorbitol.

When formulating compounds of the invention for oral administration, itcan be desirable to utilize gastroretentive formulations to enhanceabsorption from the gastrointestinal (GI) tract. A formulation which isretained in the stomach for several hours can release compounds of theinvention slowly and provide a sustained release that can be used inmethods of the invention. Disclosure of such gastro-retentiveformulations are found in Klausner, E. A., Lavy, E., Barta, M.,Cserepes, E., Friedman, M., Hoffman. A., 2003 “Novel gastroretentivedosage forms: evaluation of gastroretentivity and its effect on levodopain humans.” Pharm. Res. 20, 1466-73; Hoffman, A., Stepensky, D., Lavy,E., Eyal, S., Klausner, E., Friedman, M. 2004 “Pharmacokinetic andpharmacodynamic aspects of gastroretentive dosage forms” Int. J. Pharm.11, 141-53; Streubel, A., Siepmann, J., Bodmeier, R., 2006“Gastroretentive drug delivery systems” Expert Opin. Drug Deliver. 3,217-3; and Chavanpatil, M. D., Jain, P., Chaudhari, S., Shear, R.,Vavia, P. R., “Novel sustained release, swellable and bioadhesivegastroretentive drug delivery system for olfoxacin” Int. J. Pharm. 2006epub March 24. Expandable, floating and bioadhesive techniques can beutilized to maximize absorption of the compounds of the invention.

The compounds of the invention can be formulated for parenteraladministration (i.e., by injection, for example bolus injection orcontinuous infusion) and can be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions can take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol.

For injectable formulations, the vehicle can be chosen from those knownin art to be suitable, including aqueous solutions or oil suspensions,or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil,as well as elixirs, mannitol, dextrose, or a sterile aqueous solution,and similar pharmaceutical vehicles. The formulation can also comprisepolymer compositions which are biocompatible, biodegradable, such aspoly(lactic-co-glycolic)acid. These materials can be made into micro ornanospheres, loaded with drug and further coated or derivatized toprovide superior sustained release performance. Vehicles suitable forperiocular or intraocular injection include, for example, suspensions oftherapeutic agent in injection grade water, liposomes and vehiclessuitable for lipophilic substances. Other vehicles for periocular orintraocular injection are well known in the art.

In a preferred aspect, the composition is formulated in accordance withroutine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition can also include a solubilizingagent and a local anesthetic such as lidocaine to ease pain at the siteof the injection. Generally, the ingredients are supplied eitherseparately or mixed together in unit dosage form, for example, as a drylyophilized powder or water free concentrate in a hermetically sealedcontainer such as an ampoule or sachette indicating the quantity ofactive agent. Where the composition is to be administered by infusion,it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients can be mixed prior toadministration.

When administration is by injection, the active compound can beformulated in aqueous solutions, specifically in physiologicallycompatible buffers such as Hanks solution, Ringer's solution, orphysiological saline buffer. The solution can contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Alternatively,the active compound can be in powder form for constitution with asuitable vehicle, i.e., sterile pyrogen-free water, before use. Inanother aspect, the pharmaceutical composition does not comprise anadjuvant or any other substance added to enhance the immune responsestimulated by the peptide. In another aspect, the pharmaceuticalcomposition comprises a substance that inhibits an immune response tothe peptide. Methods of formulation are known in the art, for example,as disclosed in Remington's Pharmaceutical Sciences, latest edition,Mack Publishing Co., Easton P.

In addition to the formulations described previously, the agents canalso be formulated as a depot preparation. Such long acting formulationscan be administered by implantation or transcutaneous delivery (forexample subcutaneously or intramuscularly), intramuscular injection oruse of a transdermal patch. Thus, for example, the agents can beformulated with suitable polymeric or hydrophobic materials (for exampleas an emulsion in an acceptable oil) or ion exchange resins, or assparingly soluble derivatives, for example, as a sparingly soluble salt.

In another aspect, pharmaceutical compositions comprising one or moreagents of the present invention exert local and regional effects whenadministered topically or injected at or near particular sites ofinfection. Direct topical application, i.e., of a viscous liquid,solution, suspension, dimethylsulfoxide (DMSO)-based solutions,liposomal formulations, gel, jelly, cream, lotion, ointment,suppository, foam, or aerosol spray, can be used for localadministration, to produce for example local and/or regional effects.Pharmaceutically appropriate vehicles for such formulation include, forexample, lower aliphatic alcohols, polyglycols (i.e., glycerol orpolyethylene glycol), esters of fatty acids, oils, fats, silicones, andthe like. Such preparations can also include preservatives (i.e.,p-hydroxybenzoic acid esters) and/or antioxidants (i.e., ascorbic acidand tocopherol). See also Dermatological Formulations: Percutaneousabsorption, Barry (Ed.), Marcel Dekker Incl, 1983. In another aspect,local/topical formulations comprising a fatty acid synthesis pathwayinhibitor i.e., an inhibitor of FASN gene expression or FASN proteinactivity, are used to treat epidermal or mucosal viral infections.

Pharmaceutical compositions of the present invention can contain acosmetically or dermatologically acceptable carrier. Such carriers arecompatible with skin, nails, mucous membranes, tissues and/or hair, andcan include any conventionally used cosmetic or dermatological carriermeeting these requirements. Such carriers can be readily selected by oneof ordinary skill in the art. In formulating skin ointments, an agent orcombination of agents of the instant invention can be formulated in anoleaginous hydrocarbon base, an anhydrous absorption base, awater-in-oil absorption base, an oil-in-water water-removable baseand/or a water-soluble base. Examples of such carriers and excipientsinclude, but are not limited to, humectants (i.e., urea), glycols (i.e.,propylene glycol), alcohols (i.e., ethanol), fatty acids (i.e., oleicacid), surfactants (i.e., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(i.e., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Ointments and creams can, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions can be formulated with an aqueous or oily base and willin general also containing one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See, i.e.,U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can beconstructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

Lubricants which can be used to form pharmaceutical compositions anddosage forms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (i.e., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

The compositions according to the present invention can be in any formsuitable for topical application, including aqueous, aqueous-alcoholicor oily solutions, lotion or serum dispersions, aqueous, anhydrous oroily gels, emulsions obtained by dispersion of a fatty phase in anaqueous phase (O/W or oil in water) or, conversely, (W/O or water inoil), microemulsions or alternatively microcapsules, microparticles orlipid vesicle dispersions of ionic and/or nonionic type. Thesecompositions can be prepared according to conventional methods. Otherthan the agents of the invention, the amounts of the variousconstituents of the compositions according to the invention are thoseconventionally used in the art. These compositions in particularconstitute protection, treatment or care creams, milks, lotions, gels orfoams for the face, for the hands, for the body and/or for the mucousmembranes, or for cleansing the skin. The compositions can also consistof solid preparations constituting soaps or cleansing bars.

Compositions of the present invention can also contain adjuvants commonto the cosmetic and dermatological fields, such as hydrophilic orlipophilic gelling agents, hydrophilic or lipophilic active agents,preserving agents, antioxidants, solvents, fragrances, fillers,sunscreens, odor-absorbers and dyestuffs. The amounts of these variousadjuvants are those conventionally used in the fields considered and,for example, are from about 0.01% to about 20% of the total weight ofthe composition. Depending on their nature, these adjuvants can beintroduced into the fatty phase, into the aqueous phase and/or into thelipid vesicles.

In another aspect, ocular viral infections can be effectively treatedwith ophthalmic solutions, suspensions, ointments or inserts comprisingan agent or combination of agents of the present invention. Eye dropscan be prepared by dissolving the active ingredient in a sterile aqueoussolution such as physiological saline, buffering solution, etc., or bycombining powder compositions to be dissolved before use. Other vehiclescan be chosen, as is known in the art, including but not limited to:balance salt solution, saline solution, water soluble polyethers such aspolyethyene glycol, polyvinyls, such as polyvinyl alcohol and povidone,cellulose derivatives such as methylcellulose and hydroxypropylmethylcellulose, petroleum derivatives such as mineral oil and whitepetrolatum, animal fats such as lanolin, polymers of acrylic acid suchas carboxypolymethylene gel, vegetable fats such as peanut oil andpolysaccharides such as dextrans, and glycosaminoglycans such as sodiumhyaluronate. If desired, additives ordinarily used in the eye drops canbe added. Such additives include isotonizing agents (i.e., sodiumchloride, etc.), buffer agent (i.e., boric acid, sodium monohydrogenphosphate, sodium dihydrogen phosphate, etc.), preservatives (i.e.,benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.),thickeners (i.e., saccharide such as lactose, mannitol, maltose, etc.;i.e., hyaluronic acid or its salt such as sodium hyaluronate, potassiumhyaluronate, etc.; i.e., mucopolysaccharide such as chondroitin sulfate,etc.; i.e., sodium polyacrylate, carboxyvinyl polymer, crosslinkedpolyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose,carboxymethyl cellulose, hydroxy propyl cellulose or other agents knownto those skilled in the art).

The solubility of the components of the present compositions can beenhanced by a surfactant or other appropriate co-solvent in thecomposition. Such cosolvents include polysorbate 20, 60, and 80,Pluronic F68, F-84 and P-103, cyclodextrin, or other agents known tothose skilled in the art. Such co-solvents can be employed at a level offrom about 0.01% to 2% by weight.

The compositions of the invention can be packaged in multidose form.Preservatives can be preferred to prevent microbial contamination duringuse. Suitable preservatives include: benzalkonium chloride, thimerosal,chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol,edetate disodium, sorbic acid, Onamer M, or other agents known to thoseskilled in the art. In the prior art ophthalmic products, suchpreservatives can be employed at a level of from 0.004% to 0.02%. In thecompositions of the present application the preservative, preferablybenzalkonium chloride, can be employed at a level of from 0.001% to lessthan 0.01%. i.e. from 0.001% to 0.008%, preferably about 0.005% byweight. It has been found that a concentration of benzalkonium chlorideof 0.005% can be sufficient to preserve the compositions of the presentinvention from microbial attack.

In another aspect, viral infections of the ear can be effectivelytreated with otic solutions, suspensions, ointments or insertscomprising an agent or combination of agents of the present invention.

In another aspect, the agents of the present invention are delivered insoluble rather than suspension form, which allows for more rapid andquantitative absorption to the sites of action. In general, formulationssuch as jellies, creams, lotions, suppositories and ointments canprovide an area with more extended exposure to the agents of the presentinvention, while formulations in solution, i.e., sprays, provide moreimmediate, short-term exposure.

In another aspect relating to topical/local application, thepharmaceutical compositions can include one or more penetrationenhancers. For example, the formulations can comprise suitable solid orgel phase carriers or excipients that increase penetration or helpdelivery of agents or combinations of agents of the invention across apermeability barrier, i.e., the skin. Many of thesepenetration-enhancing compounds are known in the art of topicalformulation, and include, i.e., water, alcohols (i.e., terpenes likemethanol, ethanol, 2-propanol), sulfoxides (i.e., dimethyl sulfoxide,decylmethyl sulfoxide, tetradecylmethyl sulfoxide), pyrrolidones (i.e.,2-pyrrolidone, N-methyl-2-pyrrolidone, N-(2-hydroxyethyl)pyrrolidone),laurocapram, acetone, dimethylacetamide, dimethylformamide,tetrahydrofurfuryl alcohol, L-α-amino acids, anionic, cationic,amphoteric or nonionic surfactants (i.e., isopropyl myristate and sodiumlauryl sulfate), fatty acids, fatty alcohols (i.e., oleic acid), amines,amides, clofibric acid amides, hexamethylene lauramide, proteolyticenzymes, α-bisabolol, d-limonene, urea and N,N-diethyl-m-toluamide, andthe like. Additional examples include humectants (i.e., urea), glycols(i.e., propylene glycol and polyethylene glycol), glycerol monolaurate,alkanes, alkanols, ORGELASE, calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and/or otherpolymers. In another aspect, the pharmaceutical compositions willinclude one or more such penetration enhancers.

In another aspect, the pharmaceutical compositions for local/topicalapplication can include one or more antimicrobial preservatives such asquaternary ammonium compounds, organic mercurials, p-hydroxy benzoates,aromatic alcohols, chlorobutanol, and the like.

Gastrointestinal viral infections can be effectively treated withorally- or rectally delivered solutions, suspensions, ointments, enemasand/or suppositories comprising an agent or combination of agents of thepresent invention.

Respiratory viral infections can be effectively treated with aerosolsolutions, suspensions or dry powders comprising an agent or combinationof agents of the present invention. Administration by inhalation isparticularly useful in treating viral infections of the lung, such as anHRV infection. The aerosol can be administered through the respiratorysystem or nasal passages. For example, one skilled in the art willrecognize that a composition of the present invention can be suspendedor dissolved in an appropriate carrier, i.e., a pharmaceuticallyacceptable propellant, and administered directly into the lungs using anasal spray or inhalant. For example, an aerosol formulation comprisinga fatty acid synthesis pathway inhibitor i.e., an inhibitor of FASN geneexpression or FASN protein activity, can be dissolved, suspended oremulsified in a propellant or a mixture of solvent and propellant, i.e.,for administration as a nasal spray or inhalant. Aerosol formulationscan contain any acceptable propellant under pressure, such as acosmetically or dermatologically or pharmaceutically acceptablepropellant, as conventionally used in the art.

An aerosol formulation for nasal administration is generally an aqueoussolution designed to be administered to the nasal passages in drops orsprays. Nasal solutions can be similar to nasal secretions in that theyare generally isotonic and slightly buffered to maintain a pH of about5.5 to about 6.5, although pH values outside of this range canadditionally be used. Antimicrobial agents or preservatives can also beincluded in the formulation.

An aerosol formulation for inhalations and inhalants can be designed sothat the agent or combination of agents of the present invention iscarried into the respiratory tree of the subject when administered bythe nasal or oral respiratory route. Inhalation solutions can beadministered, for example, by a nebulizer. Inhalations or insufflations,comprising finely powdered or liquid drugs, can be delivered to therespiratory system as a pharmaceutical aerosol of a solution orsuspension of the agent or combination of agents in a propellant, i.e.,to aid in disbursement. Propellants can be liquefied gases, includinghalocarbons, for example, fluorocarbons such as fluorinated chlorinatedhydrocarbons, hydrochlorofluorocarbons, and hydrochlorocarbons, as wellas hydrocarbons and hydrocarbon ethers.

Halocarbon propellants useful in the present invention includefluorocarbon propellants in which all hydrogens are replaced withfluorine, chlorofluorocarbon propellants in which all hydrogens arereplaced with chlorine and at least one fluorine, hydrogen-containingfluorocarbon propellants, and hydrogen-containing chlorofluorocarbonpropellants. Halocarbon propellants are described in Johnson, U.S. Pat.No. 5,376,359, issued Dec. 27, 1994; Byron et al., U.S. Pat. No.5,190,029, issued Mar. 2, 1993; and Purewal et al., U.S. Pat. No.5,776,434, issued Jul. 7, 1998. Hydrocarbon propellants useful in theinvention include, for example, propane, isobutane, n-butane, pentane,isopentane and neopentane. A blend of hydrocarbons can also be used as apropellant. Ether propellants include, for example, dimethyl ether aswell as the ethers. An aerosol formulation of the invention can alsocomprise more than one propellant. For example, the aerosol formulationcan comprise more than one propellant from the same class, such as twoor more fluorocarbons; or more than one, more than two, more than threepropellants from different classes, such as a fluorohydrocarbon and ahydrocarbon. Pharmaceutical compositions of the present invention canalso be dispensed with a compressed gas, i.e., an inert gas such ascarbon dioxide, nitrous oxide or nitrogen.

Aerosol formulations can also include other components, for example,ethanol, isopropanol, propylene glycol, as well as surfactants or othercomponents such as oils and detergents. These components can serve tostabilize the formulation and/or lubricate valve components.

The aerosol formulation can be packaged under pressure and can beformulated as an aerosol using solutions, suspensions, emulsions,powders and semisolid preparations. For example, a solution aerosolformulation can comprise a solution of an agent of the invention such asa fatty acid synthesis pathway inhibitor i.e., an inhibitor of FASN geneexpression or FASN protein activity, in (substantially) pure propellantor as a mixture of propellant and solvent. The solvent can be used todissolve the agent and/or retard the evaporation of the propellant.Solvents useful in the invention include, for example, water, ethanoland glycols. Any combination of suitable solvents can be use, optionallycombined with preservatives, antioxidants, and/or other aerosolcomponents.

An aerosol formulation can also be a dispersion or suspension. Asuspension aerosol formulation can comprise a suspension of an agent orcombination of agents of the instant invention, i.e., a fatty acidsynthesis pathway inhibitor, i.e., an inhibitor of FASN gene expressionor FASN protein activity, and a dispersing agent. Dispersing agentsuseful in the invention include, for example, sorbitan triolcate, oleylalcohol, oleic acid, lecithin and corn oil. A suspension aerosolformulation can also include lubricants, preservatives, antioxidant,and/or other aerosol components.

An aerosol formulation can similarly be formulated as an emulsion. Anemulsion aerosol formulation can include, for example, an alcohol suchas ethanol, a surfactant, water and a propellant, as well as an agent orcombination of agents of the invention, i.e., a fatty acid synthesispathway, i.e., an inhibitor of FASN gene expression or FASN proteinactivity. The surfactant used can be nonionic, anionic or cationic. Oneexample of an emulsion aerosol formulation comprises, for example,ethanol, surfactant, water and propellant. Another example of anemulsion aerosol formulation comprises, for example, vegetable oil,glyceryl monostearate and propane.

The compounds of the invention can be formulated for administration assuppositories. A low melting wax, such as a mixture of triglycerides,fatty acid glycerides, Witepsol S55 (trademark of Dynamite NobelChemical, Germany), or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the invention can be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

It is envisioned additionally, that the compounds of the invention canbe attached releasably to biocompatible polymers for use in sustainedrelease formulations on, in or attached to inserts for topical,intraocular, periocular, or systemic administration. The controlledrelease from a biocompatible polymer can be utilized with a watersoluble polymer to form a instillable formulation, as well. Thecontrolled release from a biocompatible polymer, such as for example,PLGA microspheres or nanospheres, can be utilized in a formulationsuitable for intra ocular implantation or injection for sustainedrelease administration, as well. Any suitable biodegradable andbiocompatible polymer can be used.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are present in aneffective amount, i.e., in an amount effective to achieve therapeuticand/or prophylactic benefit in a host with at least one viral infectionor in a subject having cancer. The actual amount effective for aparticular application will depend on the condition or conditions beingtreated, the condition of the subject, the formulation, and the route ofadministration, as well as other factors known to those of skill in theart. Determination of an effective amount of a fatty acid synthesispathway inhibitor i.e., an inhibitor of FASN gene expression or FASNprotein activity, is well within the capabilities of those skilled inthe art, in light of the disclosure herein, and will be determined usingroutine optimization techniques.

The effective amount for use in humans can be determined from animalmodels. For example, a dose for humans can be formulated to achievecirculating, liver, topical and/or gastrointestinal concentrations thathave been found to be effective in animals. One skilled in the art candetermine the effective amount for human use, especially in light of theanimal model experimental data described herein. Based on animal data,and other types of similar data, those skilled in the art can determinethe effective amounts of compositions of the present inventionappropriate for humans.

The effective amount when referring to an agent or combination of agentsof the invention will generally mean the dose ranges, modes ofadministration, formulations, etc., that have been recommended orapproved by any of the various regulatory or advisory organizations inthe medical or pharmaceutical arts (i.e., FDA, AMA) or by themanufacturer or supplier.

Further, appropriate doses for a fatty acid synthesis pathway inhibitori.e., an inhibitor of FASN gene expression or FASN protein activity, canbe determined based on in vitro experimental results. For example, thein vitro potency of an agent in inhibiting a fatty acid synthesispathway component, i.e., FASN gene expression or FASN protein activity,provides information useful in the development of effective in vivodosages to achieve similar biological effects.

In another aspect, administration of agents of the present invention canbe intermittent, for example administration once every two days, everythree days, every five days, once a week, once or twice a month, and thelike. In another aspect, the amount, forms, and/or amounts of thedifferent forms can be varied at different times of administration.

A person of skill in the art would be able to monitor in a patient theeffect of administration of a particular agent. For example, HIV viralload levels can be determined by techniques standard in the art, such asmeasuring CD4 cell counts, and/or viral levels as detected by PCR. Othertechniques would be apparent to one of skill in the art.

Having now generally described various aspects and aspects of theinvention, the same will be more readily understood through reference tothe following examples which are provided by way of illustration, andare not intended to be limiting, unless specified.

EXAMPLES

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures herein described. It is to be understood thatthe examples are provided to illustrate certain embodiments and that nolimitation to the scope of the disclosure is intended thereby. It is tobe further understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure and/or scope of the appended claims

Example 1—FASN Inhibition by Compounds of the Present Disclosure

Determination of FASN Biochemical Activity:

The FASN enzyme was isolated from SKBr3 cells. SKBr3 is a human breastcancer cell-line with high levels of FASN expression. It is estimatedthat FASN comprises about 25% of the cytosolic proteins in this cellline. SKBr3 cells were homogenized in a dounce homogenizer thencentrifuged for 15 minutes at 4° C. to remove particulate matter. Thesupernatant was then analyzed for protein content, diluted to theappropriate concentration, and used to measure FASN activity. Thepresence of FASN was confirmed by western blot analysis. A similarmethod for isolation of FASN from SKBr3 cells is described in Teresa. P.et al. (Clin. Cancer Res. 2009; 15(24), 7608-7615).

FASN activity of the SKBr3 cell extract was determined by measuringeither NADPH oxidation or the amount of thiol-containing coenzyme A(CoA) released during the fatty acid synthase reaction. The dye CPM(7-diethylamino-3-(4′-maleimidyl-phenyl)-4-methylcoumarin) contains athiol reactive group that increases its fluorescence emission onreaction with the sulfhydryl group of CoA. The biochemical activitiesshown in Table 1 were determined using the fluorescence measurement ofCoA release via a procedure described in Chung C. C. et al. (Assay andDrug Development Technologies, 2008, 6(3), 361-374).

Example 2—Antiviral Activity

The antiviral activity of Formula (I-Z) was assessed using the HCV1breplicon system:

The replicon was constructed using the ET (luc-ubi-neo/ET) cell line, aHuh7 human hepatoma cell line harboring an HCV replicon with a stableluciferase (Luc) reporter and three cell culture-adaptive mutations(Pietschmann, et al (2002) J. Virol. 76:4008-4021). The HCV repliconantiviral evaluation assay examined the effects of compounds at sixhalf-log concentrations. Human interferon alpha-2b was included in eachrun as a positive control compound. Sub-confluent cultures of the ETline were plated out into 96-well plates that are dedicated for theanalysis of cell numbers (cytotoxicity) or antiviral activity and thenext day drugs were added to the appropriate wells. Cells were processed72 hr later when the cells were still sub-confluent. EC₅₀(concentrations inhibiting the replicon by 50% and 90%, respectively),IC₅₀ (concentration decreasing cell viability by 50%) and SI (selectiveindex: IC₅₀/EC₅₀) values were determined. HCV RNA replicon levels wereassessed as either HCV RNA replicon-derived Luc activity or as HCV RNAby TaqMan RT-PCR. Two methods were used to estimate cell counts(cytotoxicity). When the Luc assay system was employed, the colorimetricCytoTox-1 cell proliferation assay (Promega) was used to estimate cellnumbers, while ribosomal RNA (rRNA) levels determined via TaqMan RT-PCRwere used as an indication of cell numbers in the RNA-based assay. Asummary of the results is listed below in Table 2.

TABLE 2 Replicon EC50 Cell IC50 Selectivity Method (μM) (μM) IndexLuciferase activity 0.017 >32 >1882 TaqMan RT-PCR 0.105 >100 >952

Example 3—FASN Inhibition Correlates to HCV Inhibition

The antiviral activities of 15 compounds of the present disclosure(numbers correlate to the compounds in Table 1) were measured using theHCV replicon system. Replicon cell line 1b (HCV 1b/Luc-Neo replicon (1bCon1 with Firefly gene integrated)) was established following publishedmethods (Lohmann et al. (1999) Science 285(5424): 110-113, Lohmann etal. (2001) J. Virol. 75(3):1437-1449 and Qi et al. (2009) Antiviral Res.81(2):166-173) using Huh7 by G418 selection. The replicon was assembledusing synthetic gene fragments. The GT1b line has PV-EKT and harbors 3adaptive mutations E1202G(NS3), T1280I(NS3), K1846T(NS4B) and thebackbone is Con1. The culture medium was:

-   -   a) DMEM supplement with 10% FBS, G418 (250 g/ml), streptomycin        (100 μg/ml)/penicillin (100 U/ml), L-glutamine (100×), NEAA        (100×)    -   b) Media prepared as follows:        -   i) 500 ml DMEM media (Gibco, Cat#11960-077)        -   ii) 57 ml Fetal Bovine Serum (Gibco, Cat#16140-071)        -   iii) 5.7 ml Penicillin-Streptomycin (Gibco, Cat#15140-122)        -   iv) 5.7 ml MEM non-essential amino acids (Gibco,            Cat#111140-050)        -   v) 5.7 ml L-glutamine (Gibco, Cat#125030-081)        -   vi) 574.1 ml media+2.87 ml 50 mg/ml G418 [final 0.25 mg/ml]            (Gibco, Cat#10131-027)

Compounds were dissolved in DMSO to provide a 10 mM stock or used fromstock DMSO solutions. Compounds were diluted to generate 10-point halflog (3.16-fold) serial dilutions for assay in 384-well plates (Echoqualified 384-well PP (Labcyte Cat#P-05525)) plus DMSO in duplicate.This experiment was repeated three times on three different days.

Cells were harvested when confluency reached 90%-100%. Cellconcentrations were adjusted to 8×10⁴ cells/ml and added to 384-wellwhite assay microplates (tissue-culture treated—Greiner Cat#781080) toreach a final cell density of 2,000 cells/well. Plates were incubated at5% CO₂ and 37° C. for 72 hours.

After 72 hours of incubation Bright-Glo Luciferase reagent (Promega,cat#E2650) and Cell Titer Flo (Promega, cat#G6080/1/2) were prepared andstored in the dark while equilibrating to room temperature. Treatedcells were likewise equilibrated to room temperature. 10 μL of CellTiter Flo was added to each well of compound-treated cells and incubatedin microtiter plates for approx. 0.5 hours. Cell viability was measuredusing an Envision reader (available from Perkin Elmer) to estimatecytotoxicity. 30 μL of firefly luciferase substrate were added to eachwell and chemiluminescence was measured as an indicator of the extent ofHCV replication.

The anti-replicon activity (% inhibition) is calculated using theequation:

${\% \mspace{14mu} {Inhibition}} = {\left( {1 - \frac{{Cmpd} - {Control}}{{DMSO} - {Control}}} \right) \times 100}$

Cytotoxicity is calculated using the equation:

${\% \mspace{14mu} {Cytotoxicity}} = {\left( {1 - \frac{{Cmpd} - {Background}}{{DMSO} - {Background}}} \right) \times 100.}$

There was determined to be a correlation between potency of FASNinhibition and antiviral activity as illustrated in Table 3 below andFIG. 1. It is noted that none of the compounds caused significantcytotoxicity.

TABLE 3 Molecule Biochemical IC50 (μM) Antiviral EC50 (μM) 1 0.230 0.4252 0.065 0.192 12 0.370 1.003 14 0.263 0.260 20 0.022 0.011 27 0.1070.153 43 0.110 0.154 55 0.035 0.034 58 0.025 0.078 67 0.090 0.270 680.100 0.301 70 0.037 0.099 73 0.040 0.117 152 0.052 0.072 343 0.6000.624

Example 4—FASN Inhibitors Retain Activity Against HCV Mutants thatConfer Resistance to Direct-Acting Antiviral Agents

One of the major challenges in treating hepatitis C is the rapidemergence of resistance in response to direct-acting antiviral agents.Resistance typically results when the virus generates a point mutantthat supports essential viral functions but prevents antiviral agentsfrom binding. Three FASN inhibitors (compounds 55, 20, and 70) weretested for their ability to inhibit mutants of HCV that conferresistance to representative antiviral agents. Each of these mutants wasintroduced into a GT1b construct based on a Con1 backbone containing thePVIRES-Luciferase Ubi-Neo gene and harboring 1 adaptive mutation(S22041), (Lohmann et al. (1999) Science 285(5424): 110-113, Lohmann etal. (2001) J. Virol. 75(3): 1437-1449 and Qi et al. (2009) AntiviralRes. 81(2): 166-173). Antiviral activities were measured by the methoddescribed in Example 3.

The studied mutations are shown in Table 4 below.

TABLE 4 Studied Mutations Mutant Reference NS3 A156T Susser et al J.Clin. Virol. 52(4), 321-327 (2011) and references therein NS3 R155KSusser et al J. Clin. Virol. 52(4), 321-327 (2011) and referencestherein NS4B H94R Rai et al. Antiviral Res. 90, 93-101 (2011) NS5AY393HFridell et al. Antimicrob. Agents Chemother. 54(9), 3641-3650 (2010)NS5B M423I (non-nucleoside site) Troke et al. Antimicrob. AgentsChemother. 56(3), 1331-1341 (2012) NS5B S282T (nucleoside site) Dutartreet al. Antimicrob. Agents Chemother. 50(12), 4161-4169 (2006)

A known NS4B allosteric inhibitor (Compound A), a known NS5A inhibitor(Compound B), a known non-nucleoside NS5B inhibitor (Compound C), aknown NS3/NS4A protease inhibitor (Compound D) and a known nucleosideNS5B inhibitor (Compound E) were tested in parallel with the FASNinhibitors of the present disclosure to confirm the performance of theresistance mutations.

Antiviral EC₅₀'s for the various compounds against the panel of mutants,along with the relative shift in EC₅₀ relative to the GT1b wild-typereplicon are shown below. Normal assay variation is ±3-4 fold. EC₅₀shifts outside this range imply resistance and are indicated in bold.The 3 FASN inhibitors retain activity across the panel of mutants,whereas the direct-acting antiviral agents display resistance againstmutations in their respective binding sites.

TABLE 5 Antiviral EC₅₀'s. EC₅₀ (nM) 1b Wild NS3 NS3 NS4B NS5A NS5B NS5BCompound Type A156T R155K H94R Y93H M423I S282T 55 49.63 143.00 156.1067.31 109.40 19.22 73.30 20 16.71 44.06 25.46 17.02 32.00 19.70 25.60 7039.18 49.97 43.91 36.00 108.90 58.69 56.90 Compound A 261.00 232.20209.60 2813.00 n.t. 126.60 n.t. Compound B 0.01 0.01 n.t. n.t. 0.28 0.010.01 Compound D 0.67 105.00 236.60 0.39 n.t. 1.54 n.t. Compound C 4.274.57 8.43 4.61 3.00 34.09 3.00 Compound E 583.70 890.90 n.t. n.t. 1069.0159.30 15650.0

TABLE 6 Fold shift in EC50 relative to wild-type HCV Fold shift in EC50relative to wild-type Binding NS3 NS3 NS4B NS5A NS5B NS5B Compound SiteA156T R155K H94R Y93H M423I S282T 55 2.88 3.15 1.36 2.20 0.39 1.48 202.64 1.52 1.02 1.92 1.18 1.53 70 1.28 1.12 0.92 2.78 1.50 1.45 CompoundA NS4B 0.89 0.80 10.78  n.t. 0.49 n.t. Compound B NS5A 1.00 n.t. n.t.35.13  0.75 0.88 Compound D NS3/4A 156.46 352.56 0.58 n.t. 2.29 n.t.Compound C NS5B 1.07 1.98 1.08 0.70 7.99 0.70 (non-nuc) Compound E NS5B1.53 n.t. n.t. 1.83 0.27 26.81  (nuc)

Example 5—FASN Inhibitors Useful in Combination Therapies

This example describes the in vitro antiviral activity and cytotoxicityof the compound of Formula (V-K) in combination with IFN-α, Ribavirin,Compounds B, C, D and E against an HCV GT1b replicon cell line.

Materials:

Virus:

The GT1b replicon plasmid was assembled using synthetic gene fragments.The replicon genome contains PVIRES-Luciferase Ubi-Neo gene segments andharbors 1 adaptive mutation (S22041), and the backbone is Con1. Thereplicon GT1b cell line was established by the following publishedmethods.

Medium and Reagents:

Table 7 below provides details regarding the culture medium reagentsused in this example.

TABLE 7 List of culture medium regents Reagent Vendor Catalogue NumberDimethyl sulfoxide (DMSO) Sigma Cat #34869-100ML DMEM Invitrogen Cat#11960-044 Fetal Bovine Serum (FBS) Gibco Cat #16140 Pen-StrepInvitrogen Cat #15140-122 MEM non-essential amino acids Invitrogen Cat#11140-050 L-Glutamin Invitrogen Cat #25030-081 G418 (geneticin) GibcoCat #10131-027 Trypsin/EDTA Invitrogen Cat #25200-072 DPBS/ModifiedHyclone SH30028.01B 96-well cell plate Greiner Cat #655090CellTiter-Fluor ™ Promega Cat #G6082 Bright-Glo Promega Cat #E264B

Analytical Instruments:

The following analytical instruments were used to perform the assays ofthis example:

-   -   POD-810    -   Topcount (PE)    -   Envision (PE)    -   Multidrop (Thermo)

Methods:

Preparation of Compound Plates for Single Compound Testing:

Compounds were supplied as dry powders and were reconstituted in DMSO togenerate stock solutions. The POD-810 system was used to generate10-point half log (3.16-fold) serial dilutions for the assay in 96-wellplates. The highest test concentrations are detailed for each compoundin Table 8.

Assay Protocol (Single Compounds):

Each compound was assayed with 3.16-fold (half log) serial dilutions for10 concentrations plus DMSO in duplicate. HCV replicon GT1b cells wereharvested and adjusted to a cell concentration of 8E+04 cells/ml. AMultidrop was used to plate 100 μL/well into 96 assay microplates toreach a final cell density of 8,000 cells/well. Plates were incubated at5% CO₂, 37° C. for 72 hours.

At the end of the 72 hour incubation, antiviral activity andcytotoxicity were measured. Bright-Glo Luciferase reagent and Cell TiterFlo were prepared and stored in dark while equilibrating to roomtemperature. The cell plates were allowed to equilibrate to roomtemperature as well. A Multidrop was used to add 20 μL Cell Titer Flo toeach well of compound-treated and compound-free cells. The plates areincubated for 1 hour, and cell viability is measured on an Envisionreader for cytoxicity calculation. Fifty microliters of fireflyluciferase substrate are added to each well, incubated for 2 minutes,and chemiluminescence is measured for EC₅₀ calculation.

The anti-replicon activity (% inhibition) was calculated using thefollowing equation:

% Inhibition=[1−((Compound−background)/(DMSO−background))×100].

Test Compounds and Assay Setup for Two-Compound Combination Studies:

The DMSO stocks of the compounds used in the single compound testingwere also used in this analysis. Combination dilution matrixes weregenerated by POD-810 in 96-well assay microplates. The POD-810 systemwas used to generate 7-point, 2-fold serial dilutions in a matrixformat. The maximum concentration tested for each compound is detailedbelow.

TABLE 8 Expected activities and upper concentrations of compounds testedin single-agent and combination studies Highest Highest concentrationconcentration Expected GT1b for single-agent for combination CompoundEC50 (μM) testing (μM) testing (μM) (V-K) 0.060 10.0 0.100 Compound D0.0014 0.032 0.0032 Compound C 0.018 10.0 0.032 Compound B 0.0000090.001 0.000032 Compound E 4.030 100.0 10.0 IFN 64.94 IU/ml 1000 IU/ml10.0 IU/ml Ribavirin 26.830 320.0 100.0

The compound of Formula (V-K) was tested alone and in combination withcompounds detailed in Table 9. Each compound was also tested alone as asingle agent.

TABLE 9 Combinations of compounds for in vitro evaluation. RegimenCombination 1 (V-K) + Compound D 2 (V-K) + Compound C 3 (V-K) + CompoundB 5 (V-K) + Compound E 6 (V-K) + IFN-α 7 (V-K) + RBV

Assay Setup (Two-Drug Combinations):

Each compound was assayed with 2-fold serial dilutions for 7concentrations in matrix format plus each drug alone. HCV replicon GT1bcells were harvested and adjusted to a cell concentration of 8E+04cells/ml. A Multidrop was used to plate 100 μL into 96 assay microplatesto reach a final cell density of 8,000 cells/well. Plates were incubatedat 5% CO₂, 37° C. for 72 hours.

At the end of the 72 hour incubation, antiviral activity andcytotoxicity were measured. Bright-Glo Luciferase reagent and Cell TiterFlo were prepared and stored in the dark while allowing to them toequilibrate to room temperature. The cells plates were allowed toequilibrate to room temperature as well. A Multidrop was used to add 20μL Cell Titer Flo to each well of compound-treated and compound-freecells. The plates were incubated for 1 hour, and cell viability wasmeasured on an Envision reader for cytotoxicity calculation. The liquidwas then removed from the plates, after which 50 μL PBS and 50 μLfirefly luciferase substrate solution were added to each well, after a2-minute incubation period, chemiluminescence (for HCV replicationcalculation) was measured. The data were analyzed using MacSynergy™ II.

Assay Results:

Activity and Cytotoxicity of the Compounds.

The EC₅₀ and CC₅₀ values are summarized below in Table 10.

TABLE 10 EC₅₀ and CC₅₀ of Each Test Compound GT1b EC₅₀ Expected EC₅₀CC₅₀ Compound (μM) (μM) (μM) (V-K) 0.04 0.06 >10 Compound D 0.00210.0014 >0.032 Compound C 0.006 0.018 >10 Compound B 0.0000120.000009 >0.001 Compound E 2.41 4.03 >100 IFN-α (IU/mL) 1.34 1 >1000 RBV32.75 26.83 239

Combination Effect. The combination effect of the compound pairs wascalculated using MacSynergy™ II and those results are summarized inTable 11 below.

TABLE 11 Summary of the combination effects of the compound pairsMacSynergy ™ II Compd 1 Compd 2 SYNERGY PLOT (95%) (top conc) (top conc)SYNERGY Log volume ANTAGONISM Log volume (V-K) Compound D 16.7 1.51−13.03 −1.18 Compound C 2.93 0.27 −9.2 −0.83 Compound B 6.75 0.61 −7.11−0.64 Compound E 1.08 0.1 −7.81 −0.73 IFN-α 5.44 0.49 −24.88 −2.25 RBV1.64 0.15 −3.52 −0.32 * None of the combinations cause cytotoxicity.

CONCLUSIONS

The Z factors of the compound pairs summarized in Table 12 indicate thatthe assay quality is better than the QC standard.

TABLE 12 Summary of the Z factor of compound pairs Z factor Drug PairsPlate-1 Plate-2 Plate-3 (V-K) + Compound D 0.68 0.86 0.83 (V-K) +Compound C 0.66 0.78 0.65 (V-K) + Compound B 0.70 0.83 0.84 (V-K) +Compound E 0.72 0.76 0.74 (V-K) + IFN-α 0.75 0.70 0.66 (V-K) + RBV 0.780.78 0.72

The EC₅₀ values of the individual compounds in the combination matrix(summarized in Table 13) are consistent with the EC₅₀ data in obtainedfor single-compound inhibition Table 10.

TABLE 13 Summary of EC₅₀ of single dose in compound combination GT1bEC₅₀ (μM) EC₅₀ (μM) of single in dose dose in drug Compound rangingassay combination (V-K) 0.04 0.07 Compound D 0.0021 0.0017 Compound C0.006 0.009 Compound B 0.000012 0.000009 Compound E 2.41 1.79IFN-α(IU/mL) 1.34 3.43 RBV 32.75 31.63

The compound of Formula (V-K) was demonstrated to have additiveantiviral activity without enhanced cytotoxicity in combination withagents representing a variety of mechanisms. These results aresummarized in Table 14 below.

TABLE 14 Summary of antiviral mechanisms that are additive with thecompound of Formula (V-K). The term “direct-acting antiviral” (“DAA”)refers to a compound that binds to and inhibits a viral protein, ratherthan a host protein. Molecule Mechanism Class IFN-α Cellular defenseHost RBV Multiple Host Compound D HCV Protease DAA Compound B NS5AInhibitor DAA Compound C NS5B Inhibitor DAA Compound E NS5B InhibitorDAA

IFN-α and RBV represent current standard-of-care for treating HepatitisC infection, and the HCV protease inhibitors Telaprevir and Boceprivirhave recently been approved. The additive antiviral activity and lack ofenhanced cytotoxicity in combination with IFN-α and RBV further suggestthat compounds of this invention will not interfere with critical hostprocesses such as cellular defense (IFN-α) or guanidine nucleotidebiosynthesis (RBV). Compounds of this invention such as the compound ofFormula (V-K) should therefore be therapeutically useful if administeredin combination regimens with current standard of care. Moreover, theadditive antiviral activities observed with Compound B, Compound C, andCompound E suggest that molecules of this invention such as the compoundof Formula (V-K) can be productively combined with agents currently indevelopment that target newer mechanisms (i.e., NS5A and NS5Binhibitors).

Example 6—Anti-Tumor Activity—Multiplexed Cytotoxicity Assay

Cells were grown in RPMI1640, 10% FBS, 2 mM L-alanyl-L-Glutamine, 1 mMNa pyruvate or a special medium in a humidified atmosphere of 5% CO₂ at37° C. Cells were seeded into 384-well plates and incubated in ahumidified atmosphere of 5% CO₂ at 37° C. Compounds were added 24 hourspost cell seeding. At the same time, a time zero untreated cell platewas generated.

After a 72 hour incubation period, cells were fixed and stained withfluorescently labeled antibodies and nuclear dye to allow visualizationof nuclei, apoptotic cells and mitotic cells. Apoptotic cells weredetected using an anti-active caspase-3 antibody. Mitotic cells weredetected using an anti phospho-histone-3 antibody.

Compounds were serially diluted in half-log (3.16-fold) increments andassayed over 10 concentrations in a final assay concentration of 0.1%DMSO from the highest test concentration specified in the sampleinformation chapter. Automated fluorescence microscopy was carried outusing a GE Healthcare IN Cell Analyzer 1000, and images were collectedwith a 4× objective.

Twelve bit tiff images were acquired using the InCell Analyzer 1000 3.2and analyzed with Developer Toolbox 1.6 software. EC₅₀ and IC₅₀ valueswere calculated using nonlinear regression to fit data to a sigmoidal 4point, 4 parameter One-Site dose response model, where: y(fit)=A+[(B−A)/(I+((C/x)̂D))]. Curve-fitting, EC₅₀/IC₅₀ calculations andreport generation are performed using a custom data reduction engineMathIQ based software (AIM).

The multiplexed cytotoxicity assay uses a cell image based analysistechnique where cells are fixed and stained with fluorescently labeledantibodies and nuclear dye to visualize nuclei, and apoptotic andmitotic cells. Apoptotic cells are detected using an anti-activecaspase-3 antibody. Mitotic cells are detected using an antiphospho-histone-3 antibody.

Cell proliferation is measured by the signal intensity of theincorporated nuclear dye. The cell proliferation assay output isreferred to as the relative cell count. To determine the cellproliferation end point, the cell proliferation data output istransformed to percent of control (POC) using the following formula:

POC=relative cell count(compound wells)/relative cell count(vehiclewells)×100

Time zero non-treated plate is used to determine number of doublings in72 hour assay period: Number of doublings in 72 hours=LN[Cell number (72hrs end point)*Cell number (time zero)]/LN(2). The output of eachbiomarker is fold increase over vehicle background normalized to therelative cell count in each well.

The activated caspase-3 marker labels cells from early to late stageapoptosis. The output is shown as a fold increase of apoptotic cellsover vehicle background normalized to the relative cell count in eachwell. Concentrations of test compound that cause a 5-fold induction inthe caspase-3 signal indicates significant apoptosis induction. Wellswith concentrations higher than the relative cell count IC₉₅ areeliminated from the caspase3 induction analysis.

The phospho-histone-3 marker labels mitotic cells. The output is shownas a fold induction of mitotic cells over vehicle background normalizedto the relative cell count in each well. When the fold induction ofmitotic cell signal over background is ˜1, there is “no effect” on thecell cycle. Two or more fold increase in phospho-histone-3 signal overvehicle background indicates significant test compound induction ofmitotic block.

Two or more fold decrease in the phospho-histone-3 signal may indicateGU/S block only when cytotoxicity levels are below the measured relativecell count IC₉₅. When 2 or more fold decrease in the phospho-histone-3signal are observed at concentrations higher than the relative cellcount IC₉₅, the decrease in mitotic cell counts are most likely due to amore general cytotoxicity effect rather than a true G1/S phase block.Wells with concentrations higher than the relative cell count IC₉₅ areeliminated from the phospho-histone-3 analysis.

Cell proliferation measured by relative cell counts were the criteriafor positive response.

Apoptosis:

>5-fold increase in activated caspase-3 signal indicates an apoptoticresponse

Mitosis:

>2-fold increase in phospho-histone-3 indicates mitotic block

<2-fold decrease in phospho-histone-3 indicates G1/S block

TABLE 15 Results Max Biochemical G1/S cell Max G2/M Apoptosis IC₅₀ cycleblock cell cycle Fold Compound (μM) (μM) block Induction 205 0.220 0.1601.36 2.39 95 0.030 0.012 0.94 2.45 142 0.140 0.031 1.28 2.34 153 0.0600.014 1.17 2.55 427 0.080 0.019 1.00 2.39 42 0.070 0.013 1.09 2.20 480.170 0.027 1.27 2.20 156 0.030 0.031 1.28 2.59 182 0.150 0.030 1.542.07 183 0.170 0.031 1.00 2.40

While preferred aspects of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch aspects are provided by way of example only. Numerous variations,changes, and substitutions will now occur to those skilled in the artwithout departing from the invention. It should be understood thatvarious alternatives to the aspects of the invention described hereincan be employed in practicing the invention. It is intended that thefollowing claims define the scope of the invention and that methods,compounds, and structures within the scope of these claims and theirequivalents be covered thereby.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A compound of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl.
 2. The compound ofclaim 1, wherein R²⁴ is C₁-C₄ straight or branched alkyl or —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein t is 0 or
 1. 3.The compound of claim 1, wherein R²¹ is halogen, C₁-C₄ straight orbranched alkyl or C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom.
 4. The compound ofclaim 1, wherein R³ is H or halogen.
 5. The compound of claim 1, 1wherein R¹ is halogen, —CN or C₁-C₂ haloalkyl.
 6. The compound of claim1, wherein both L¹ and L² are N.
 7. The compound of claim 1, wherein R²¹is C₁-C₂ alkyl or C₃-C₅ cycloalkyl and R²² is C₁-C₂ alkyl.
 8. Thecompound of claim 1, wherein R²¹ is C₃-C₅ cycloalkyl and R²² is C₁-C₂alkyl.
 9. The compound of claim 1, wherein R²⁴ is —(C₁-C₂alkyl)_(t)-O—(C₁-C₂ alkyl) wherein t is 0 or
 1. 10. The compound ofclaim 1, wherein R²¹ is C₃-C₅ cycloalkyl, R²² is C₁-C₂ alkyl and R²⁴ isC₁-C₂ alkyl.
 11. The compound of claim 10, wherein R²¹ is cyclobutyl,R²² is C₁-C₂ alkyl and R²⁴ is C₁-C₂ alkyl.
 12. The compound of claim 1,wherein R²¹ is cyclobutyl.
 13. The compound of claim 1, wherein R³ is Hor F.
 14. The compound of claim 1, wherein R¹ is —CN.
 15. The compoundof claim 1, wherein R¹ is —CF₃.
 16. The compound of claim 1, wherein R²²is H, methyl or ethyl.
 17. The compound of claim 16, wherein R²² is H.18. The compound of claim 1, wherein R²² is methyl.
 19. The compound ofclaim 1, wherein R¹ is —CN, each R² is H, R³ is H or F, R²¹ is C₃-C₄cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ is methyl, ethyl,hydroxymethyl, methoxymethyl, 2-methoxyethyl.
 20. The compound of claim1, wherein R¹ is —CN, each R² is H, R³ is H or F, R²¹ is C₃-C₄cycloalkyl, R²² is methyl, L¹ and L² are N, and R²⁴ is methoxy orethoxy.
 21. The compound of claim 1, wherein R¹ is —CN, each R² is H, R³is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is CH, L² is N,and R²⁴ is methyl, ethyl, hydroxymethyl, methoxymethyl, or2-methoxyethyl.
 22. The compound of claim 1, wherein R¹ is —CN, each R²is H, R³ is H or F, R²¹ is C₃-C₄ cycloalkyl, R²² is methyl, L¹ is N, L²is CH, and R²⁴ is methyl, ethyl, hydroxymethyl, methoxymethyl, or2-methoxyethyl.
 23. The compound of claim 1, having a formula selectedfrom the group consisting of:


24. A compound of Formula (X):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH or halogen; L³ is C(R₆₀)₂, O or NR⁵⁰;each R₆₀ is independently H, —OH, —CN, —O_(t)—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl), or —C(O)—N(R₆₀)₂ wherein: t is 0or 1, and the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; each R⁵⁰ is independently H, —C(O)—O_(t)—(C₁-C₄ straight orbranched alkyl), —C(O)—O_(t)—(C₃-C₅ cyclic alkyl), —C₃-C₅ cyclic alkyloptionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R⁵⁰¹)₂,C₁-C₄ straight or branched alkyl wherein: t is 0 or 1, and the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; n is 1,2 or 3; m is 1 or 2; R²¹ is H, halogen, C₁-C₄ straight or branchedalkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅ cycloalkyl optionally includesan oxygen or nitrogen heteroatom R²² is H, halogen, C₁-C₂ alkyl; eachR²⁶ is independently —OH, —CN, halogen, C₁-C₄ straight or branchedalkyl, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), —(C₁-C₄alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl), —C(O)—O_(t)—(C₁-C₄alkyl), or —C(O)—N(R⁵⁰¹)₂ wherein: t is 0 or 1, and the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; s is 0, 1 or 2;each R⁶⁰¹ and R⁵⁰¹ is independently H or C₁-C₄ straight or branchedalkyl; and wherein two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ optionally jointo form a ring wherein the two of R²⁶, R⁶⁰, R⁵⁰, R⁵⁰¹ and R⁶⁰¹ may betwo R²⁶, two R⁶⁰, two R⁵⁰, two R⁵⁰¹ or two R⁶⁰¹. 25-45. (canceled)
 46. Acompound having Formula (VI-J):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, or C₁-C₂ alkyl; R³⁵ is—C(O)—R³⁵¹, —C(O)—NHR³⁵¹, —C(O)—O—R³⁵¹ or S(O)₂R³⁵¹; and R³⁵¹ is C₁-C₆straight or branched alkyl, cycloalkyl, heterocyclyl, aryl orheteroaryl. 47-66. (canceled)
 67. A compound having Formula (XI):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: the C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently H, halogen or C₁-C₄ straight orbranched alkyl; R³ is H, —OH, or halogen; R²¹ is cyclobutyl,azetidin-1-yl, or cyclopropyl; R²² is H, halogen, C₁-C₂ alkyl; and R³⁵¹is C₁-C₂ alkyl or C₂—O—(C₁ or C₂ alkyl). 68-80. (canceled)
 81. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier, excipient, or diluent.
 82. A methodof treating viral infection in a subject comprising administering to thesubject a therapeutically effective amount of a compound of claim
 1. 83.The method of claim 82, wherein the viral infection is a hepatitis Cinfection.
 84. The method of claim 82, wherein the viral infection is arespiratory viral infection.
 85. The method of claim 84, wherein therespiratory virus is selected from the group consisting of RSV, CMV,Flu, PIV3, HSV1/2, HRV16, and Cox A24.
 86. A method of treating acondition characterized by disregulation of a fatty acid synthasefunction in a subject by administering to the subject a therapeuticallyeffective amount of a compound of claim
 1. 87. A method of treatingcancer in a subject comprising administering to the subject atherapeutically effective amount of a compound of claim
 1. 88. Themethod of claim 87, wherein the cancer is selected from the groupconsisting of breast cancer; antle cell lymphoma; renal cell carcinoma;acute myelogenous leukemia (AML); chronic myelogenous leukemia (CML);diffuse large B cell lymphoma (DLBCL); sarcoma; rhabdomyosarcoma;ovarian cancer; endometrial tumors; non small cell lung carcinoma(NSCLC); small cell, squamous, large cell and adenocarcinoma; lungcancer; colon cancer; colorectal tumors; KRAS-mutated colorectal tumors;gastric carcinomas; hepatocellular tumors; liver tumors; primarymelanomas; pancreatic cancer; prostate carcinoma; thyroid carcinoma;follicular thyroid carcinoma; anaplastic large cell lymphoma (ALCL);hamaratomas, angiomyelolipomas, TSC-associated and sporadiclymphangioleiomyomatosis: Cowden's disease (multiple hamaratomasyndrome); sclerosing hemangioma; Peutz-Jeghers syndrome (PJS); head andneck cancer; neurofibromatosis; macular degeneration; macular edema;myeloid leukemia; systemic lupus; and autoimmune lymphoproliferativesyndrome (ALPS).
 89. The method of claim 88, wherein the cancer isbreast cancer, lung cancer, ovarian cancer, pancreatic cancer or coloncancer.
 90. The method of claim 89, wherein the cancer is breast cancer.91. The method of claim 89, wherein the cancer is pancreatic cancer. 92.A method of treating a condition characterized by disregulation of afatty acid synthase pathway in a subject by administering to the subjecta therapeutically effective amount of: (i) a first therapeutic agent,wherein the first therapeutic agent is compound of Formula (IX):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, —CN,halogen, C₁-C₄ straight or branched alkyl, —O—(C₃-C₅ cycloalkyl),—O—(C₁-C₄ straight or branched alkyl) wherein: C₃-C₅ cycloalkyloptionally includes an oxygen or nitrogen heteroatom; and when R¹ is notH, —CN or halogen, it is optionally substituted with one or morehalogens; each R² is independently hydrogen, halogen or C₁-C₄ straightor branched alkyl; R³ is H, —OH, or halogen; R²¹ is H, halogen, C₁-C₄straight or branched alkyl, C₃-C₅ cycloalkyl wherein the C₃-C₅cycloalkyl optionally includes an oxygen or nitrogen heteroatom; R²² isH, halogen, or C₁-C₂ alkyl; R²⁴ is H, C₁-C₄ straight or branched alkyl,—(C₁-C₄ alkyl)_(t)-OH, —(C₁-C₄ alkyl)_(t)-O_(t)—(C₃-C₅ cycloalkyl), or—(C₁-C₄ alkyl)_(t)-O—(C₁-C₄ straight or branched alkyl) wherein: t is 0or 1; the C₃-C₅ cycloalkyl optionally includes an oxygen or nitrogenheteroatom; L¹ is CR²³ or N; L² is CH or N; at least one of L¹ or L² isN; and R²³ is H or C₁-C₄ straight or branched alkyl; and (ii) a secondtherapeutic agent.
 93. The method of claim 92 wherein the secondtherapeutic agent is a cancer therapeutic agent selected frompaclitaxel, doxorubicin, vincristine, actinomycin D, altretamine,asparaginase, bleomycin, busulphan, cabazitaxel, capecitabine,carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide,cytarabine, dacarbazine, daunorubicin, docetaxel, epirubicin, etoposide,fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin,ifosfamide, irinotecan, lomustine, melphalan, mercaptopurine,methotrexate, mitomycin, mitozantrone, oxaliplatin, procarbazine,steroids, streptozocin, taxotere, tamozolomide, thioguanine, thiotepa,tomudex, topotecan, treosulfan, uracil-tegufur, vinblastine, vindesine,nivolumab, pembrolizumab, MPDL3280A, MEDI4736, olaparib, erlotinib,necitumumab, traztuzamab, pertuzamab, lapatinib, crizotinib,cabozantinib, onartuamab, ramucirumab, bevacizumab, enzalutamide,abiraterone, tamoxifen, cobimetinib, vemurafenib, everolimus, lapatinib,trastuzumab, Kadyzla, sirolimus, avastin, nexavar, sutent, exemtesane,femora, enzalutamide, bicalutamide, Tafinlar, and Zelboraf.
 94. Themethod of claim 92, wherein the first and second therapeutic agents areadministered in the same dosage unit.
 95. The method of claim 92,wherein the first and second therapeutic agents are administered inseparate dosage units.